62 results on '"Steven X Hou"'
Search Results
2. Long noncoding RNAs heat shock RNA omega nucleates TBPH and promotes intestinal stem cell differentiation upon heat shock
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Yinfeng Guo, Meng Wang, Jiaxin Zhu, Qiaoming Li, Haitao Liu, Yang Wang, and Steven X. Hou
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Science - Published
- 2024
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3. Arf1 Ablation in Colorectal Cancer Cells Activates a Super Signal Complex in DC to Enhance Anti‐Tumor Immunity
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Handong Ma, Wanqi Fang, Qiaoming Li, Yuetong Wang, and Steven X. Hou
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anti‐tumor immunity ,T cell infiltration ,NLRP3 ,cGAS‐STING ,oxLDL ,Science - Abstract
Abstract The anti‐tumor immune response relies on interactions among tumor cells and immune cells. However, the molecular mechanisms by which tumor cells regulate DCs as well as DCs regulate T cells remain enigmatic. Here, the authors identify a super signaling complex in DCs that mediates the Arf1‐ablation‐induced anti‐tumor immunity. They find that the Arf1‐ablated tumor cells release OxLDL, HMGB1, and genomic DNA, which together bound to a coreceptor complex of CD36/TLR2/TLR6 on DC surface. The complex then is internalized into the Rab7‐marked endosome in DCs, and further joined by components of the NF‐κB, NLRP3 inflammasome and cGAS‐STING triple pathways to form a super signal complex for producing different cytokines, which together promote CD8+ T cell tumor infiltration, cross‐priming and stemness. Blockage of the HMGB1‐gDNA complex or reducing expression in each member of the coreceptors or the cGAS/STING pathway prevents production of the cytokines. Moreover, depletion of the type I IFNs and IL‐1β cytokines abrogate tumor regression in mice bearing the Arf1‐ablated tumor cells. These findings reveal a new molecular mechanism by which dying tumor cells releasing several factors to activate the triple pathways in DC for producing multiple cytokines to simultaneously promote DC activation, T cell infiltration, cross‐priming and stemness.
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- 2023
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4. An MST4‐pβ‐CateninThr40 Signaling Axis Controls Intestinal Stem Cell and Tumorigenesis
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Hui Zhang, Moubin Lin, Chao Dong, Yang Tang, Liwei An, Junyi Ju, Fuping Wen, Fan Chen, Meng Wang, Wenjia Wang, Min Chen, Yun Zhao, Jixi Li, Steven X. Hou, Xinhua Lin, Lulu Hu, Wenbo Bu, Dianqing Wu, Lin Li, Shi Jiao, and Zhaocai Zhou
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cancer stem cells ,colorectal cancer ,intestinal stem cells ,MST4‐pβ‐cateninThr40 signaling axis ,targeted therapy ,Science - Abstract
Abstract Elevated Wnt/β‐catenin signaling has been commonly associated with tumorigenesis especially colorectal cancer (CRC). Here, an MST4‐pβ‐cateninThr40 signaling axis essential for intestinal stem cell (ISC) homeostasis and CRC development is uncovered. In response to Wnt3a stimulation, the kinase MST4 directly phosphorylates β‐catenin at Thr40 to block its Ser33 phosphorylation by GSK3β. Thus, MST4 mediates an active process that prevents β‐catenin from binding to and being degraded by β‐TrCP, leading to accumulation and full activation of β‐catenin. Depletion of MST4 causes loss of ISCs and inhibits CRC growth. Mice bearing either MST4T178E mutation with constitutive kinase activity or β‐cateninT40D mutation mimicking MST4‐mediated phosphorylation show overly increased ISCs/CSCs and exacerbates CRC. Furthermore, the MST4‐pβ‐cateninThr40 axis is upregulated and correlated with poor prognosis of human CRC. Collectively, this work establishes a previously undefined machinery for β‐catenin activation, and further reveals its function in stem cell and tumor biology, opening new opportunities for targeted therapy of CRC.
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- 2021
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5. Supplemental materials and methods and figure legends from The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues
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Wu-Min Deng, Renjie Jiao, Steven X. Hou, Xiankun Zeng, Yi-Chun Huang, William Hunt Palmer, Zhiqiang Shu, Dongyu Jia, Hanqing Chen, and Gengqiang Xie
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Legends and methods.
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- 2023
6. Supplementary table 1 from The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues
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Wu-Min Deng, Renjie Jiao, Steven X. Hou, Xiankun Zeng, Yi-Chun Huang, William Hunt Palmer, Zhiqiang Shu, Dongyu Jia, Hanqing Chen, and Gengqiang Xie
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Supplementary Table 1: The mRNA level changes of representative components or targets of JAK-STAT, JNK, and Notch signaling pathways in snr1-RNAi tumorous wing discs relative to control wildtype wing discs.
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- 2023
7. Supplementary file 1 from The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues
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Wu-Min Deng, Renjie Jiao, Steven X. Hou, Xiankun Zeng, Yi-Chun Huang, William Hunt Palmer, Zhiqiang Shu, Dongyu Jia, Hanqing Chen, and Gengqiang Xie
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Supplementary file 1
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- 2023
8. Supplementary Figures 1-13 from The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues
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Wu-Min Deng, Renjie Jiao, Steven X. Hou, Xiankun Zeng, Yi-Chun Huang, William Hunt Palmer, Zhiqiang Shu, Dongyu Jia, Hanqing Chen, and Gengqiang Xie
- Abstract
Supplementary figure 1: Snr1 is required for cell survival in Drosophila wing imaginal disc. Supplementary figure 2: Tumorigenic overgrowth in wing discs carrying snr1-depletion by tissue-specific Gal4 drivers. Supplementary figure 3: Coexpression of rpr and p35 does not induce neoplastic tumorigenic overgrowth in the wing disc. Supplementary figure 4: Wing discs with snr1 loss shows neoplastic overgrowth. Supplementary figure 5: Tumorigenic overgrowth in the wing disc with mosaic clones of snr1 mutation. Supplementary figure 6: Depletion of brm or osa causes apoptotic phenotype in wing pouch region. Supplementary figure 7: Subcellular localization in salivary gland cells. Supplementary figure 8: Knockdown of other components of the SWI/SNF complex does not affect trafficking signaling. Supplementary figure 9: Transmembrane proteins are not accumulated in brm- or osa-depleted cells. Supplementary figure 10: Notch signaling is not upregulated in brm- or osa-RNAi cells. Supplementary figure 11: Depletion of brm or osa does not change JAK-STAT signaling activity. Supplementary figure 12: JNK signaling is barely affected in brm- or osa-depleted cells. Supplementary figure 13: Knockdown of dilp8 or mmp1 does not suppress snr1 depletion-induced tumorigenic overgrowth.
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- 2023
9. Data from The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues
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Wu-Min Deng, Renjie Jiao, Steven X. Hou, Xiankun Zeng, Yi-Chun Huang, William Hunt Palmer, Zhiqiang Shu, Dongyu Jia, Hanqing Chen, and Gengqiang Xie
- Abstract
Components of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in various human cancers, yet only SMARCB1/hSNF5, a core member of the SWI/SNF complex, is mutated in malignant rhabdoid tumors (MRT). How SMARCB1/hSNF5 functions differently from other members of the SWI/SNF complex remains unclear. Here, we use Drosophila imaginal epithelial tissues to demonstrate that Snr1, the conserved homolog of human SMARCB1/hSNF5, prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling cascades. Removal of Snr1 resulted in neoplastic tumorigenic overgrowth in imaginal epithelial tissues, whereas depletion of any other members of the SWI/SNF complex did not induce similar phenotypes. Unlike other components of the SWI/SNF complex that were detected only in the nucleus, Snr1 was observed in both the nucleus and the cytoplasm. Aberrant regulation of multiple signaling pathways, including Notch, JNK, and JAK/STAT, was responsible for tumor progression upon snr1-depletion. Our results suggest that the cytoplasmic Snr1 may play a tumor suppressive role in Drosophila imaginal tissues, offering a foundation for understanding the pivotal role of SMARCB1/hSNF5 in suppressing MRT during early childhood. Cancer Res; 77(4); 862–73. ©2017 AACR.
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- 2023
10. Neuronal accumulation of peroxidated lipids promotes demyelination and neurodegeneration through the activation of the microglial NLRP3 inflammasome
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Qingjun Tian, Hyun-hee Shin, Weiqin Yin, Guohao Wang, Steven X. Hou, and Wei Lu
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Aging ,Microglia ,Chemistry ,Neurodegeneration ,Neuroscience (miscellaneous) ,Inflammasome ,Human brain ,medicine.disease ,Proinflammatory cytokine ,Cell biology ,medicine.anatomical_structure ,Lipid droplet ,medicine ,Small GTPase ,Geriatrics and Gerontology ,Neuroinflammation ,medicine.drug - Abstract
Peroxidated lipids accumulate in the presence of reactive oxygen species and are linked to neurodegenerative diseases. Here we find that neuronal ablation of ARF1, a small GTPase important for lipid homeostasis, promoted accumulation of peroxidated lipids, lipid droplets and ATP in the mouse brain and led to neuroinflammation, demyelination and neurodegeneration, mainly in the spinal cord and hindbrain. Ablation of ARF1 in cultured primary neurons led to an increase in peroxidated lipids in co-cultured microglia, activation of the microglial NLRP3 inflammasome and release of inflammatory cytokines in an Apolipoprotein E-dependent manner. Deleting the Nlrp3 gene rescued the neurodegenerative phenotypes in the neuronal Arf1-ablated mice. We also observed a reduction in ARF1 in human brain tissue from patients with amyotrophic lateral sclerosis and multiple sclerosis. Together, our results uncover a previously unrecognized role of peroxidated lipids released from damaged neurons in activation of a neurotoxic microglial NLRP3 pathway that may play a role in human neurodegeneration. The authors demonstrate that release of peroxidated lipids from mouse neurons following ablation of the small GTPase ARF1 leads to activation of a neurotoxic microglial NLRP3 pathway and show that ARF1 is reduced in human brain tissue from patients with neurodegenerative diseases.
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- 2021
11. Arf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice
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Jiangsha Zhao, Dayong Liu, Junji Xu, Steven X. Hou, Wanjun Chen, Weiqin Yin, and Guohao Wang
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Male ,0301 basic medicine ,Cancer therapy ,T-Lymphocytes ,General Physics and Astronomy ,Metastasis ,Mice ,0302 clinical medicine ,Alarmins ,lcsh:Science ,Gastrointestinal Neoplasms ,Mice, Knockout ,Mice, Inbred BALB C ,Gene knockdown ,Multidisciplinary ,Cancer stem cells ,Chemistry ,Liver Neoplasms ,Vaccination ,Endoplasmic Reticulum Stress ,Cancer metabolism ,Mitochondria ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Female ,Infiltration (medical) ,Lipolysis ,Science ,Antineoplastic Agents ,Article ,General Biochemistry, Genetics and Molecular Biology ,Gastrointestinal cancer ,03 medical and health sciences ,Immune system ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Lipid metabolism ,Dendritic Cells ,General Chemistry ,Lipid Metabolism ,medicine.disease ,Mice, Inbred C57BL ,Tamoxifen ,030104 developmental biology ,Cell culture ,Cancer cell ,Cancer research ,ADP-Ribosylation Factor 1 ,lcsh:Q - Abstract
Cancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid metabolism sustains cells enriched with CSCs and its ablation induces anti-tumor immune responses in mice. Notably, Arf1 ablation in cancer cells induces mitochondrial defects, endoplasmic-reticulum stress, and the release of damage-associated molecular patterns (DAMPs), which recruit and activate dendritic cells (DCs) at tumor sites. The activated immune system finally elicits antitumor immune surveillance by stimulating T-cell infiltration and activation. Furthermore, TCGA data analysis shows an inverse correlation between Arf1 expression and T-cell infiltration and activation along with patient survival in various human cancers. Our results reveal that Arf1-pathway knockdown not only kills CSCs but also elicits a tumor-specific immune response that converts dying CSCs into a therapeutic vaccine, leading to durable benefits., Cancer stem cells (CSC) have been shown as the origin for therapeutic resistance and patient relapse. Here, the authors show that targeting Arf1-mediated lipid metabolism in CSC induces cell death but also an immunogenic anti-cancer response.
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- 2020
12. Disruption of the lipolysis pathway results in stem cell death through a sterile immunity-like pathway in adult Drosophila
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Poonam Aggarwal, Zilun Liu, Guang Qian Cheng, Shree Ram Singh, Chunmei Shi, Ying Chen, Ling V. Sun, and Steven X. Hou
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Adenosine Triphosphate ,Cell Death ,Lipolysis ,Neoplastic Stem Cells ,Animals ,Drosophila ,General Biochemistry, Genetics and Molecular Biology - Abstract
We previously showed that the Arf1-mediated lipolysis pathway sustains stem cells and cancer stem cells (CSCs); its ablation resulted in necrosis of stem cells and CSCs, which further triggers a systemic antitumor immune response. Here we show that knocking down Arf1 in intestinal stem cells (ISCs) causes metabolic stress, which promotes the expression and translocation of ISC-produced damage-associated molecular patterns (DAMPs; Pretaporter [Prtp] and calreticulin [Calr]). DAMPs regulate macroglobulin complement-related (Mcr) expression and secretion. The secreted Mcr influences the expression and localization of enterocyte (EC)-produced Draper (Drpr) and LRP1 receptors (pattern recognition receptors [PRRs]) to activate autophagy in ECs for ATP production. The secreted ATP possibly feeds back to kill ISCs by activating inflammasome-like pyroptosis. We identify an evolutionarily conserved pathway that sustains stem cells and CSCs, and its ablation results in an immunogenic cascade that promotes death of stem cells and CSCs as well as antitumor immunity.
- Published
- 2021
13. Arf1-Ablation-Induced Neuronal Damage Promotes Neurodegeneration Through an NLRP3 Inflammasome–Meningeal γδ T cell–IFNγ-Reactive Astrocyte Pathway
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Guohao Wang, Steven X. Hou, Hyun-hee Shin, and Weiqin Yin
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Microglia ,T cell ,Neurodegeneration ,Inflammasome ,Biology ,medicine.disease ,Synapse ,medicine.anatomical_structure ,Immune system ,nervous system ,Forebrain ,medicine ,Neuroscience ,Neuroinflammation ,medicine.drug - Abstract
Neurodegenerative diseases are often initiated from neuronal injury or disease and propagated through neuroinflammation and immune response. However, the mechanisms by which injured neurons induce neuroinflammation and immune response that feedback to damage neurons are largely unknown. Here, we demonstrate that Arf1 ablation in adult mouse neurons resulted in activation of a reactive microglia–A1 astrocyte–C3 pathway in the hindbrain and midbrain but not in the forebrain, which caused demyelination, axon degeneration, synapse loss, and neurodegeneration. We further find that the Arf1-ablated neurons released peroxided lipids and ATP that activated an NLRP3 inflammasome in microglia to release IL-1β, which together with elevated chemokines recruited and activated γδT cells in meninges. The activated γδ T cells then secreted IFNγ that entered into parenchyma to activate the microglia–A1 astrocyte–C3 neurotoxic pathway for destroying neurons and oligodendrocytes. Finally, we show that the Arf1-reduction-induced neuroinflammation–IFNγ–gliosis pathway exists in human neurodegenerative diseases, particularly in amyotrophic lateral sclerosis and multiple sclerosis. This study illustrates perhaps the first complete mechanism of neurodegeneration in a mouse model. Our findings introduce a new paradigm in neurodegenerative research and provide new opportunities to treat neurodegenerative disorders.
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- 2020
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14. Glycolytic reprogramming through PCK2 regulates tumor initiation of prostate cancer cells
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Jieran Li, Teresa W.-M. Fan, Jiangsha Zhao, and Steven X. Hou
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0301 basic medicine ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,glucose metabolism ,Tumor initiation ,Biology ,Metastasis ,03 medical and health sciences ,Prostate cancer ,Prostate ,PCK2 ,Internal medicine ,mental disorders ,medicine ,cancer ,prostate ,Cancer ,medicine.disease ,3. Good health ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Tumor progression ,Cancer research ,tumorigenicity ,Phosphoenolpyruvate carboxykinase ,Research Paper ,phosphoenolpyruvate carboxykinase isoform 2 - Abstract
// Jiangsha Zhao 1 , Jieran Li 2 , Teresa W.M. Fan 2 and Steven X. Hou 1 1 The Basic Research Laboratory, National Cancer Institute, National Institutes of Health Frederick, Frederick, MD 21702, USA 2 Graduate Center of Toxicology and Cancer Biology, Center for Environmental and Systems Biochemistry, and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA Correspondence to: Steven X. Hou, email: hous@mail.nih.gov Keywords: cancer, glucose metabolism, phosphoenolpyruvate carboxykinase isoform 2, prostate, tumorigenicity Received: April 04, 2017 Accepted: May 21, 2017 Published: June 28, 2017 ABSTRACT Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein acetylation. Our data suggest PCK2 promotes tumor initiation by lowering acetyl-CoA level through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate tumors.
- Published
- 2017
15. The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues
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Hanqing Chen, Gengqiang Xie, Xiankun Zeng, Dongyu Jia, Zhiqiang Shu, Wu-Min Deng, Steven X. Hou, Yi-Chun Huang, Renjie Jiao, and William H. Palmer
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0301 basic medicine ,Cancer Research ,MAP Kinase Signaling System ,cells ,genetic processes ,Endosomes ,macromolecular substances ,Biology ,medicine.disease_cause ,Article ,law.invention ,03 medical and health sciences ,law ,medicine ,Animals ,Drosophila Proteins ,SMARCB1 ,Genetics ,Receptors, Notch ,SWI/SNF complex ,Tumor Suppressor Proteins ,SMARCB1 Protein ,Phenotype ,Cell biology ,STAT Transcription Factors ,enzymes and coenzymes (carbohydrates) ,Drosophila melanogaster ,030104 developmental biology ,Imaginal Discs ,Oncology ,Cytoplasm ,Tumor progression ,Suppressor ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,Carcinogenesis ,Signal Transduction ,Transcription Factors - Abstract
Components of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in various human cancers, yet only SMARCB1/hSNF5, a core member of the SWI/SNF complex, is mutated in malignant rhabdoid tumors (MRT). How SMARCB1/hSNF5 functions differently from other members of the SWI/SNF complex remains unclear. Here, we use Drosophila imaginal epithelial tissues to demonstrate that Snr1, the conserved homolog of human SMARCB1/hSNF5, prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling cascades. Removal of Snr1 resulted in neoplastic tumorigenic overgrowth in imaginal epithelial tissues, whereas depletion of any other members of the SWI/SNF complex did not induce similar phenotypes. Unlike other components of the SWI/SNF complex that were detected only in the nucleus, Snr1 was observed in both the nucleus and the cytoplasm. Aberrant regulation of multiple signaling pathways, including Notch, JNK, and JAK/STAT, was responsible for tumor progression upon snr1-depletion. Our results suggest that the cytoplasmic Snr1 may play a tumor suppressive role in Drosophila imaginal tissues, offering a foundation for understanding the pivotal role of SMARCB1/hSNF5 in suppressing MRT during early childhood. Cancer Res; 77(4); 862–73. ©2017 AACR.
- Published
- 2017
16. Glutamate-ammonia ligase promotes lung cancer cell growth through an enzyme-independent upregulation of CaMK2G under a glutamine-sufficient condition
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Steven X. Hou, Jiangsha Zhao, and Xiankun Zeng
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Glutamine ,chemistry.chemical_classification ,DNA ligase ,Mediator ,Downregulation and upregulation ,Cell growth ,Chemistry ,Transcription (biology) ,Cancer cell ,Transcriptional regulation ,Cell biology - Abstract
SUMMARYGlutamate-ammonia ligase (GLUL) is highly expressed in many cancer cells. Synthesizing glutamine by its enzyme function has been found to be important for supporting cancer cell survival and growth under glutamine restriction. However, GLUL’s functions under a glutamine-sufficient condition still have not been uncovered. Here we find that GLUL is highly expressed in lung cancer cells and provides survival and growth advantages under both glutamine restriction and adequacy conditions. Knocking down GLUL can block lung cancer cell growth in an enzyme-independent way when glutamine is sufficient. Mechanistically, GLUL regulates Calcium/Calmodulin Dependent Protein Kinase II Gamma (CaMK2G) expression at the transcription level, and CaMK2G is a major mediator in controlling cell growth under GLUL. The transcriptional regulation of CaMK2G is partially mediated by SMAD4. Our data unveil a new enzyme-independent function of GLUL in lung cancer cells under a glutamine-sufficient condition.
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- 2019
- Full Text
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17. Cancer Stem Cells and Stem Cell Tumors in Drosophila
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Shree Ram, Singh, Poonam, Aggarwal, and Steven X, Hou
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Disease Models, Animal ,Neoplasms ,Neoplastic Stem Cells ,Tumor Microenvironment ,Animals ,Humans ,Cell Differentiation ,Drosophila - Abstract
Accumulative studies suggest that a fraction of cells within a tumor, known as cancer stem cells (CSCs) that initiate tumors, show resistance to most of the therapies, and causes tumor recurrence and metastasis. CSCs could be either transformed normal stem cells or reprogrammed differentiated cells. The eventual goal of CSC research is to identify pathways that selectively regulate CSCs and then target these pathways to eradicate CSCs. CSCs and normal stem cells share some common features, such as self-renewal, the production of differentiated progeny, and the expression of stem-cell markers, however, CSCs vary from normal stem cells in forming tumors. Specifically, CSCs are normally resistant to standard therapies. In addition, CSCs and non-CSCs can be mutually convertible in response to different signals or microenvironments. Even though CSCs are involved in human cancers, the biology of CSCs, is still not well understood, there are urgent needs to study CSCs in model organisms. In the last several years, discoveries in Drosophila have greatly contributed to our understanding of human cancer. Stem-cell tumors in Drosophila share various properties with human CSCs and maybe used to understand the biology of CSCs. In this chapter, we first briefly review CSCs in mammalian systems, then discuss stem-cell tumors in the Drosophila posterior midgut and Malpighian tubules (kidney) and their unique properties as revealed by studying oncogenic Ras protein (Ras
- Published
- 2019
18. Cancer Stem Cells and Stem Cell Tumors in Drosophila
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Steven X. Hou, Shree Ram Singh, and Poonam Aggarwal
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Tumor microenvironment ,biology ,ved/biology ,Cellular differentiation ,ved/biology.organism_classification_rank.species ,biology.organism_classification ,medicine.disease ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,Cancer research ,medicine ,030212 general & internal medicine ,Stem cell ,Model organism ,Drosophila ,Human cancer - Abstract
Accumulative studies suggest that a fraction of cells within a tumor, known as cancer stem cells (CSCs) that initiate tumors, show resistance to most of the therapies, and causes tumor recurrence and metastasis. CSCs could be either transformed normal stem cells or reprogrammed differentiated cells. The eventual goal of CSC research is to identify pathways that selectively regulate CSCs and then target these pathways to eradicate CSCs. CSCs and normal stem cells share some common features, such as self-renewal, the production of differentiated progeny, and the expression of stem-cell markers, however, CSCs vary from normal stem cells in forming tumors. Specifically, CSCs are normally resistant to standard therapies. In addition, CSCs and non-CSCs can be mutually convertible in response to different signals or microenvironments. Even though CSCs are involved in human cancers, the biology of CSCs, is still not well understood, there are urgent needs to study CSCs in model organisms. In the last several years, discoveries in Drosophila have greatly contributed to our understanding of human cancer. Stem-cell tumors in Drosophila share various properties with human CSCs and maybe used to understand the biology of CSCs. In this chapter, we first briefly review CSCs in mammalian systems, then discuss stem-cell tumors in the Drosophila posterior midgut and Malpighian tubules (kidney) and their unique properties as revealed by studying oncogenic Ras protein (RasV12)-transformed stem-cell tumors in the Drosophila kidney and dominant-negative Notch (NDN)-transformed stem-cell tumors in the Drosophila intestine. At the end, we will discuss potential approaches to eliminate CSCs and achieve tumor regression. In future, by screening adult Drosophila neoplastic stem-cell tumor models, we hope to identify novel and efficacious compounds for the treatment of human cancers.
- Published
- 2019
19. The PDZ-GEF Gef26 regulates synapse development and function via FasII and Rap1 at the Drosophila neuromuscular junction
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Su Wang, Xiankun Zeng, Steven X. Hou, Huihui Lv, Wei Xie, Mingkuan Sun, Jinsong An, and Mengzhu Ou
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0301 basic medicine ,animal structures ,Cell Adhesion Molecules, Neuronal ,PDZ domain ,Telomere-Binding Proteins ,Morphogenesis ,Neuromuscular Junction ,Presynaptic Terminals ,Small G Protein ,Biology ,Synaptic Transmission ,Article ,Shelterin Complex ,Synapse ,03 medical and health sciences ,0302 clinical medicine ,Cell Adhesion ,Animals ,Drosophila Proteins ,Guanine Nucleotide Exchange Factors ,Cell adhesion ,fungi ,Cell Biology ,Cell biology ,030104 developmental biology ,nervous system ,030220 oncology & carcinogenesis ,Larva ,Synapses ,Rap1 ,Drosophila ,Guanine nucleotide exchange factor ,Signal transduction ,Signal Transduction - Abstract
Guanine nucleotide exchange factors (GEFs) are essential for small G proteins to activate their downstream signaling pathways, which are involved in morphogenesis, cell adhesion, and migration. Mutants of Gef26, a PDZ-GEF (PDZ domain-containing guanine nucleotide exchange factor) in Drosophila, exhibit strong defects in wings, eyes, and the reproductive and nervous systems. However, the precise roles of Gef26 in development remain unclear. In the present study, we analyzed the role of Gef26 in synaptic development and function. We identified significant decreases in bouton number and branch length at larval neuromuscular junctions (NMJs) in Gef26 mutants, and these defects were fully rescued by restoring Gef26 expression, indicating that Gef26 plays an important role in NMJ morphogenesis. In addition to the observed defects in NMJ morphology, electro-physiological analyses revealed functional defects at NMJs, and locomotor deficiency appeared in Gef26 mutant larvae. Furthermore, Gef26 regulated NMJ morphogenesis by regulating the level of synaptic Fasciclin II (FasII), a well-studied cell adhesion molecule that functions in NMJ development and remodeling. Finally, our data demonstrate that Gef26-specific small G protein Rap1 worked downstream of Gef26 to regulate the level of FasII at NMJs, possibly through a βPS integrin-mediated signaling pathway. Taken together, our findings define a novel role of Gef26 in regulating NMJ development and function.
- Published
- 2018
20. The lipolysis pathway sustains normal and transformed stem cells in adult Drosophila
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Gerald Hou, Jiangsha Zhao, Shree Ram Singh, Ying Liu, Steven X. Hou, Hanhan Liu, and Xiankun Zeng
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Male ,0301 basic medicine ,Cell Survival ,MAP Kinase Signaling System ,Lipolysis ,Cellular differentiation ,Stem cell theory of aging ,Apoptosis ,Biology ,Article ,Coat Protein Complex I ,Necrosis ,03 medical and health sciences ,Phagocytosis ,Cancer stem cell ,Cell Line, Tumor ,Autophagy ,Animals ,Drosophila Proteins ,Humans ,Cytotoxic T cell ,Cell Proliferation ,Multidisciplinary ,JNK Mitogen-Activated Protein Kinases ,Membrane Proteins ,Cell Differentiation ,rac GTP-Binding Proteins ,Cell biology ,Gastrointestinal Tract ,Endothelial stem cell ,Cell Transformation, Neoplastic ,Drosophila melanogaster ,Enterocytes ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cell culture ,Neoplastic Stem Cells ,ADP-Ribosylation Factor 1 ,Female ,Stem cell ,Energy Metabolism ,Adult stem cell - Abstract
Cancer stem cells (CSCs) may be responsible for tumour dormancy, relapse and the eventual death of most cancer patients(1). In addition, these cells are usually resistant to cytotoxic conditions. However, very little is known about the biology behind this resistance to therapeutics. Here we investigated stem-cell death in the digestive system of adult Drosophila melanogaster. We found that knockdown of the coat protein complex I (COPI)–Arf79F (also known as Arf1) complex selectively killed normal and transformed stem cells through necrosis, by attenuating the lipolysis pathway, but spared differentiated cells. The dying stem cells were engulfed by neighbouring differentiated cells through a draper–myoblast city–Rac1–basket (also known as JNK)-dependent autophagy pathway. Furthermore, Arf1 inhibitors reduced CSCs in human cancer cell lines. Thus, normal or cancer stem cells may rely primarily on lipid reserves for energy, in such a way that blocking lipolysis starves them to death. This finding may lead to new therapies that could help to eliminate CSCs in human cancers.
- Published
- 2016
21. Whole-animal genome-wide RNAi screen identifies networks regulating male germline stem cells in Drosophila
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Shree Ram Singh, Ann Marie Weideman, Steven X. Hou, Jae Lee, Qinglan Ge, Jacob Manley, Ying Liu, Gerald Hou, Brian H. K. Chan, and Hanhan Liu
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0301 basic medicine ,Male ,endocrine system ,animal structures ,Heterochromatin ,Science ,Genome, Insect ,General Physics and Astronomy ,Genes, Insect ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Germline ,Article ,Animals, Genetically Modified ,03 medical and health sciences ,Animals ,Drosophila Proteins ,Cell Lineage ,Gene Regulatory Networks ,Stem Cell Niche ,Gene ,Drosophila ,Genetics ,Multidisciplinary ,biology ,Stem Cells ,fungi ,General Chemistry ,biology.organism_classification ,High-Throughput Screening Assays ,Rnai screen ,030104 developmental biology ,Drosophila melanogaster ,Germ Cells ,Phenotype ,Organ Specificity ,Gene Knockdown Techniques ,embryonic structures ,RNA Interference ,Stem cell ,Cytokinesis ,Protein Binding ,Signal Transduction - Abstract
Stem cells are regulated both intrinsically and externally, including by signals from the local environment and distant organs. To identify genes and pathways that regulate stem-cell fates in the whole organism, we perform a genome-wide transgenic RNAi screen through ubiquitous gene knockdowns, focusing on regulators of adult Drosophila testis germline stem cells (GSCs). Here we identify 530 genes that regulate GSC maintenance and differentiation. Of these, we further knock down 113 selected genes using cell-type-specific Gal4s and find that more than half were external regulators, that is, from the local microenvironment or more distal sources. Some genes, for example, versatile (vers), encoding a heterochromatin protein, regulates GSC fates differentially in different cell types and through multiple pathways. We also find that mitosis/cytokinesis proteins are especially important for male GSC maintenance. Our findings provide valuable insights and resources for studying stem cell regulation at the organismal level., Both intrinsic and external signals regulate stem cell fate. Here, the authors perform a genome-wide RNAi screen to identify regulators of testis germline stem cells (GSC) in Drosophila, finding more than half of the genes were external regulators and heterochromatin/cytokinesis proteins mediated GSC fate.
- Published
- 2016
22. The cell polarity protein Scrib functions as a tumor suppressor in liver cancer
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Mallikarjun Patil, Shweta Kapil, Bal Krishan Sharma, Steven X. Hou, Sawsan Elattar, Jinling Yuan, Ande Satyanarayana, and Ravindra Kolhe
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0301 basic medicine ,Pathology ,Gene Expression ,Molecular oncology ,Mice ,0302 clinical medicine ,Medicine ,hippo signaling ,Cyclin D1 ,HCC ,nuclear localization ,YAP1 ,Cell Cycle ,Liver Neoplasms ,3. Good health ,Protein Transport ,ERK ,Cell Transformation, Neoplastic ,Oncology ,Hippo signaling ,030220 oncology & carcinogenesis ,Heterografts ,Stem cell ,Liver cancer ,Protein Binding ,Signal Transduction ,Research Paper ,SCRIB ,medicine.medical_specialty ,MAP Kinase Signaling System ,Active Transport, Cell Nucleus ,Yap1 ,Protein Serine-Threonine Kinases ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Cell Line, Tumor ,Animals ,Humans ,Hippo Signaling Pathway ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,business.industry ,Tumor Suppressor Proteins ,Cancer ,Membrane Proteins ,YAP-Signaling Proteins ,medicine.disease ,Phosphoproteins ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,business ,Transcription Factors - Abstract
// Shweta Kapil 1, * , Bal Krishan Sharma 1, * , Mallikarjun Patil 1, * , Sawsan Elattar 1 , Jinling Yuan 1 , Steven X. Hou 2 , Ravindra Kolhe 3 , Ande Satyanarayana 1 1 Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA 2 Stem Cell Regulation and Animal Aging Section, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA 3 Department of Pathology, Augusta University, Augusta, GA 30912, USA * These authors contributed equally to this work Correspondence to: Ande Satyanarayana, email: sande@augusta.edu Keywords: HCC, nuclear localization, ERK, hippo signaling, Yap1 Received: January 13, 2017 Accepted: February 15, 2017 Published: February 24, 2017 ABSTRACT Scrib is a membrane protein that is involved in the maintenance of apical-basal cell polarity of the epithelial tissues. However, Scrib has also been shown to be mislocalized to the cytoplasm in breast and prostate cancer. Here, for the first time, we report that Scrib not only translocates to the cytoplasm but also to the nucleus in hepatocellular carcinoma (HCC) cells, and in mouse and human liver tumor samples. We demonstrate that Scrib overexpression suppresses the growth of HCC cells in vitro, and Scrib deficiency enhances liver tumor growth in vivo. At the molecular level, we have identified the existence of a positive feed-back loop between Yap1 and c-Myc in HCC cells, which Scrib disrupts by simultaneously regulating the MAPK/ERK and Hippo signaling pathways. Overall, Scrib inhibits liver cancer cell proliferation by suppressing the expression of three oncogenes, Yap1, c-Myc and cyclin D1, thereby functioning as a tumor suppressor in liver cancer.
- Published
- 2017
23. Corrigendum to 'The PDZ-GEF Gef26 regulates synapse development and function via FasII and Rap 1 at the Drosophila neuromuscular junction' [Exp. Cell Res. 374 (2019) 342–352]
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Xiankun Zeng, Wei Xie, Su Wang, Huihui Lv, Mingkuan Sun, Jinsong An, Mengzhu Ou, and Steven X. Hou
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Synapse ,medicine.anatomical_structure ,biology ,PDZ domain ,Cell ,medicine ,Cell Biology ,Drosophila (subgenus) ,biology.organism_classification ,Neuromuscular junction ,Function (biology) ,Cell biology - Published
- 2019
24. The Osa-containing SWI/SNF chromatin-remodeling complex regulates stem cell commitment in the adult Drosophila intestine
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Steven X. Hou, Xiankun Zeng, and Xinhua Lin
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Chromatin Immunoprecipitation ,Chromosomal Proteins, Non-Histone ,Cellular differentiation ,Notch signaling pathway ,Nerve Tissue Proteins ,Cell fate determination ,Biology ,Real-Time Polymerase Chain Reaction ,Chromatin remodeling ,Animals ,Drosophila Proteins ,Homeostasis ,Cell Lineage ,Molecular Biology ,Transcription factor ,Tissue homeostasis ,DNA Primers ,Receptors, Notch ,Stem Cells ,fungi ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Stem Cells and Regeneration ,Molecular biology ,SWI/SNF ,DNA-Binding Proteins ,Intestines ,Drosophila ,RNA Interference ,Stem cell ,Signal Transduction ,Transcription Factors ,Developmental Biology - Abstract
The proportion of stem cells versus differentiated progeny is well balanced to maintain tissue homeostasis, which in turn depends on the balance of the different signaling pathways involved in stem cell self-renewal versus lineage-specific differentiation. In a screen for genes that regulate cell lineage determination in the posterior midgut, we identified that the Osa-containing SWI/SNF (Brahma) chromatin-remodeling complex regulates Drosophila midgut homeostasis. Mutations in subunits of the Osa-containing complex result in intestinal stem cell (ISC) expansion as well as enteroendocrine (EE) cell reduction. We further demonstrated that Osa regulates ISC self-renewal and differentiation into enterocytes by elaborating Notch signaling, and ISC commitment to differentiation into EE cells by regulating the expression of Asense, an EE cell fate determinant. Our data uncover a unique mechanism whereby the commitment of stem cells to discrete lineages is coordinately regulated by chromatin-remodeling factors.
- Published
- 2013
25. Broad relays hormone signals to regulate stem cell differentiation in Drosophila midgut during metamorphosis
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Steven X. Hou and Xiankun Zeng
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media_common.quotation_subject ,Cellular differentiation ,Biology ,Animals ,Drosophila Proteins ,Progenitor cell ,Metamorphosis ,Receptor ,Molecular Biology ,Loss function ,media_common ,Receptors, Notch ,Stem Cells ,fungi ,Metamorphosis, Biological ,Development and Stem Cells ,Cell Differentiation ,Midgut ,Cell biology ,Gastrointestinal Tract ,Immunology ,Drosophila ,Stem cell ,Function (biology) ,Signal Transduction ,Transcription Factors ,Developmental Biology - Abstract
Like the mammalian intestine, the Drosophila adult midgut is constantly replenished by multipotent intestinal stem cells (ISCs). Although it is well known that adult ISCs arise from adult midgut progenitors (AMPs), relatively little is known about the mechanisms that regulate AMP specification. Here, we demonstrate that Broad (Br)-mediated hormone signaling regulates AMP specification. Br is highly expressed in AMPs temporally during the larva-pupa transition stage, and br loss of function blocks AMP differentiation. Furthermore, Br is required for AMPs to develop into functional ISCs. Conversely, br overexpression drives AMPs toward premature differentiation. In addition, we found that Br and Notch (N) signaling function in parallel pathways to regulate AMP differentiation. Our results reveal a molecular mechanism whereby Br-mediated hormone signaling directly regulates stem cells to generate adult cells during metamorphosis.
- Published
- 2012
26. Characterization of midgut stem cell- and enteroblast-specific Gal4 lines in drosophila
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Steven X. Hou, Xiankun Zeng, and Chhavi Chauhan
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inorganic chemicals ,Saccharomyces cerevisiae Proteins ,animal structures ,Cell division ,Transgene ,digestive system ,Article ,Animals, Genetically Modified ,Endocrinology ,Genetics ,Asymmetric cell division ,Animals ,Drosophila Proteins ,Transgenes ,Intestinal Mucosa ,Progenitor cell ,Fluorescent Antibody Technique, Indirect ,biology ,Stem Cells ,fungi ,Midgut ,Cell Biology ,biology.organism_classification ,Cell biology ,DNA-Binding Proteins ,Intestines ,Drosophila melanogaster ,Larva ,Stem cell ,Drosophila Protein ,Transcription Factors - Abstract
The homeostasis of Drosophila midgut is maintained by multipotent intestinal stem cells (ISCs), each of which gives rise to a new ISC and an immature daughter cell, enteroblast (EB), after one asymmetric cell division. In Drosophila, the Gal4-UAS system is widely used to manipulate gene expression in a tissue- or cell-specific manner, but in Drosophila midgut, there are no ISC- or EB-specific Gal4 lines available. Here we report the generation and characterization of Dl-Gal4 and Su(H)GBE-Gal4 lines, which are expressed specifically in the ISCs and EBs separately. Additionally, we demonstrate that Dl-Gal4 and Su(H)GBE-Gal4 are expressed in adult midgut progenitors (AMPs) and niche peripheral cells (PCs) separately in larval midgut. These two Gal4 lines will serve as invaluable tools for navigating ISC behaviors.
- Published
- 2010
27. Multipotent stem cells in the Malpighian tubules of adultDrosophila melanogaster
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Shree Ram Singh and Steven X. Hou
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Physiology ,Cellular differentiation ,Review ,Malpighian Tubules ,Aquatic Science ,Biology ,Kidney ,Models, Biological ,Cancer stem cell ,Animals ,Carcinoma, Renal Cell ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Renal stem cell ,Stem cell transplantation for articular cartilage repair ,Mammals ,Induced stem cells ,Multipotent Stem Cells ,Cell Differentiation ,Cell biology ,Drosophila melanogaster ,Multipotent Stem Cell ,Insect Science ,Animal Science and Zoology ,Stem cell ,Signal Transduction ,Adult stem cell - Abstract
SUMMARYExcretion is an essential process of an organism's removal of the waste products of metabolism to maintain a constant chemical composition of the body fluids despite changes in the external environment. Excretion is performed by the kidneys in vertebrates and by Malpighian tubules (MTs) in Drosophila. The kidney serves as an excellent model organ to investigate the cellular and molecular mechanisms underlying organogenesis. Mammals and Drosophila share common principles of renal development. Tissue homeostasis, which is accomplished through self-renewal or differentiation of stem cells, is critical for the maintenance of adult tissues throughout the lifetime of an animal. Growing evidence suggests that stem cell self-renewal and differentiation is controlled by both intrinsic and extrinsic factors. Deregulation of stem cell behavior results in cancer formation, tissue degeneration, and premature aging. The mammalian kidney has a low rate of cellular turnover but has a great capacity for tissue regeneration following an ischemic injury. However, there is an ongoing controversy about the source of regenerating cells in the adult kidney that repopulate injured renal tissues. Recently, we identified multipotent stem cells in the MTs of adult Drosophila and found that these stem cells are able to proliferate and differentiate in several types of cells in MTs. Furthermore, we demonstrated that an autocrine JAK-STAT (Janus kinase–signal transducers and activators of transcription) signaling regulates stem cell self-renewal or differentiation of renal stem cells. The Drosophila MTs provide an excellent in vivo system for studying the renal stem cells at cellular and molecular levels. Understanding the molecular mechanisms governing stem cell self-renewal or differentiation in vivo is not only crucial to using stem cells for future regenerative medicine and gene therapy, but it also will increase our understanding of the mechanisms underlying cancer formation, aging and degenerative diseases. Identifying and understanding the cellular processes underlying the development and repair of the mammalian kidney may enable more effective, targeted therapies for acute and chronic kidney diseases in humans.
- Published
- 2009
28. Lessons Learned About Adult Kidney Stem Cells From the Malpighian Tubules of Drosophila
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Steven X. Hou and Shree Ram Singh
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Mammals ,Kidney ,Malpighian tubule system ,Pathology ,medicine.medical_specialty ,animal structures ,Stem Cells ,Cellular differentiation ,fungi ,Kidney development ,General Medicine ,Malpighian Tubules ,Biology ,Kidney Neoplasms ,medicine.anatomical_structure ,Nephrology ,Multipotent Stem Cell ,medicine ,Animals ,Drosophila ,Stem cell ,Progenitor cell ,Renal stem cell - Abstract
All multicellular organisms have a specialized organ to concentrate and excrete wastes from the body. The kidneys in vertebrates and the malpighian tubules in Drosophila accomplish these functions. Mammals and Drosophila share some similar features during renal tubular development. Vertebrate kidneys are derived through the mutual induction of the ureteric bud and metanephric mesoderm, whereas the malpighian tubules of Drosophila develop from the hindgut primordium and visceral mesoderm. The vertebrate kidney also has the capacity to recover and regenerate following episodes of acute injury. Previous studies suggest that stem cells and progenitor cells may be involved in the repair and regeneration of injured renal tissue. However, studies differ as to the source of the regenerating renal cells. Recently, multipotent stem cells in Drosophila malpighian tubules were identified, and it was demonstrated that several differentiated cells in the malpighian tubules arise from these stem cells. In this article, the current understanding of kidney development and stem cell fate in mammal and Drosophila is compared. Furthermore, the potential application of the adult renal stem cells in kidney repair and the treatment of kidney cancers are discussed.
- Published
- 2008
29. The Nuclear Matrix Protein Megator Regulates Stem Cell Asymmetric Division through the Mitotic Checkpoint Complex in Drosophila Testes
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Xiankun Zeng, Steven X. Hou, Ying Liu, Jiangsha Zhao, and Shree Ram Singh
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Male ,Cancer Research ,Mad2 ,lcsh:QH426-470 ,Cell Cycle Proteins ,Biology ,Protein Serine-Threonine Kinases ,Nuclear Matrix-Associated Proteins ,Chromosome Segregation ,Testis ,Genetics ,Asymmetric cell division ,Animals ,Drosophila Proteins ,Molecular Biology ,Mitosis ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,Centrosome ,Stem Cells ,Tumor Suppressor Proteins ,Asymmetric Cell Division ,Mitotic checkpoint complex ,Nuclear matrix ,Cell biology ,Spindle apparatus ,Spindle checkpoint ,lcsh:Genetics ,Mad2 Proteins ,M Phase Cell Cycle Checkpoints ,Drosophila ,Research Article - Abstract
In adult Drosophila testis, asymmetric division of germline stem cells (GSCs) is specified by an oriented spindle and cortically localized adenomatous coli tumor suppressor homolog 2 (Apc2). However, the molecular mechanism underlying these events remains unclear. Here we identified Megator (Mtor), a nuclear matrix protein, which regulates GSC maintenance and asymmetric division through the spindle assembly checkpoint (SAC) complex. Loss of Mtor function results in Apc2 mis-localization, incorrect centrosome orientation, defective mitotic spindle formation, and abnormal chromosome segregation that lead to the eventual GSC loss. Expression of mitotic arrest-deficient-2 (Mad2) and monopolar spindle 1 (Mps1) of the SAC complex effectively rescued the GSC loss phenotype associated with loss of Mtor function. Collectively our results define a new role of the nuclear matrix-SAC axis in regulating stem cell maintenance and asymmetric division., Author Summary Like many stem cells, the adult Drosophila male GSC often divides asymmetrically to produce one new stem cell and one gonialblast. The asymmetric division of GSC is specified by perpendicular orientation of the mitotic spindle to the hub-GSC interface and localization of Apc2. Here we show that Tpr/Mtor regulates GSC self-renewal and asymmetric division through the SAC complex. We found that Mtor cell-autonomously required in both GSCs and CySCs to regulate their self-renewal. Loss of Mtor function affects expression and localization of Apc2 and E-cadherin. We further found that Mtor is required for the correct centrosome orientation, mitotic spindle formation, and chromosome segregation. These defects are rescued by SAC complex components, Mps1 and Mad2. These data together suggest that Mtor regulates GSC asymmetric division and maintenance through the mitotic spindle checkpoint complex. We suggest that disruption of the Tpr-SAC pathway might lead to chromosome instability, chromosome lagging, and aneuploidy, stem cell division defects, and thereby tumor development.
- Published
- 2015
30. The novel tumour suppressor Madm regulates stem cell competition in the Drosophila testis
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Steven X. Hou, Xiankun Zeng, Ying Liu, Shree Ram Singh, and Jiangsha Zhao
- Subjects
0301 basic medicine ,Male ,Somatic cell ,Science ,General Physics and Astronomy ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Germline ,Article ,law.invention ,03 medical and health sciences ,law ,Cell Movement ,Testis ,Animals ,Drosophila Proteins ,Progenitor cell ,Stem Cell Niche ,Regulation of gene expression ,Genetics ,Gene knockdown ,Multidisciplinary ,Stem Cells ,Tumor Suppressor Proteins ,Gene Expression Regulation, Developmental ,General Chemistry ,Cell biology ,030104 developmental biology ,Drosophila melanogaster ,Germ Cells ,Suppressor ,Female ,Stem cell ,Janus kinase - Abstract
Stem cell competition has emerged as a mechanism for selecting fit stem cells/progenitors and controlling tumourigenesis. However, little is known about the underlying molecular mechanism. Here we identify Mlf1-adaptor molecule (Madm), a novel tumour suppressor that regulates the competition between germline stem cells (GSCs) and somatic cyst stem cells (CySCs) for niche occupancy. Madm knockdown results in overexpression of the EGF receptor ligand vein (vn), which further activates EGF receptor signalling and integrin expression non-cell autonomously in CySCs to promote their overproliferation and ability to outcompete GSCs for niche occupancy. Conversely, expressing a constitutively activated form of the Drosophila JAK kinase (hopTum−l) promotes Madm nuclear translocation, and suppresses vn and integrin expression in CySCs that allows GSCs to outcompete CySCs for niche occupancy and promotes GSC tumour formation. Tumour suppressor-mediated stem cell competition presented here could be a mechanism of tumour initiation in mammals., Stem cell competition mediates the balance between tissue homeostasis and tumour formation, but how this occurs is unclear. Here, Singh et al. show that the tumour suppressor Mlfl-adaptor molecule regulates the balance between germline stem cell and somatic cyst stem cell growth in the Drosophila testis niche.
- Published
- 2015
31. Rap-GEF/Rap signaling restricts the formation of supernumerary spermathecae in Drosophila melanogaster
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Wei Liu, Su-Wan Oh, Steven X. Hou, Xiu Chen, Shree Ram Singh, and Zhiyu Zheng
- Subjects
animal structures ,Mutant ,medicine.disease_cause ,Spermatheca ,Cell Adhesion ,medicine ,Animals ,Guanine Nucleotide Exchange Factors ,Supernumerary ,RNA, Messenger ,Cell adhesion ,Drosophila ,Genetics ,Mutation ,biology ,Reproduction ,fungi ,Gene Expression Regulation, Developmental ,Genitalia, Female ,Cell Biology ,biology.organism_classification ,Phenotype ,Cell biology ,Drosophila melanogaster ,rap GTP-Binding Proteins ,Female ,Signal Transduction ,Developmental Biology - Abstract
Sperm storage in the female is a key factor for reproductive success in a variety of organisms, including Drosophila melanogaster. The spermathecae (SP) are the Drosophila organs for long-term storage. While wild-type female flies have two SP, occasionally, three or four SP have been observed in mutant flies. However, the molecular mechanism of SP formation is unknown. Here we show that loss of function of a Drosophila Rap-GEF (GEF26) result in an occurrence of the supernumerary SP; females have three SP (varies from 11 to 62% in different allele combinations) instead of the normal two SP. In addition, the Gef26 mutant flies also have ectopic wing veins and extra mechanosensory organs. The supernumerary SP phenotype of the Gef26 mutation can be enhanced by the Drosophila Rap mutations and rescued by overexpressing the cell adhesion molecule DE-cadherin. These data suggest that the Rap-GEF/Rap signaling controls the formation of supernumerary spermathecae through modulating cell adhesion in Drosophila.
- Published
- 2006
32. JAK/STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila
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Steven X. Hou, Shree Ram Singh, and Xiu Chen
- Subjects
Male ,Cell signaling ,MAP Kinase Signaling System ,PIM1 ,Biology ,Cell fate determination ,Models, Biological ,Germline ,stat ,Cell Line ,Cell Movement ,Animals ,Humans ,Cell Lineage ,Tissue Distribution ,Molecular Biology ,Body Patterning ,Cell Proliferation ,Cell growth ,Stem Cells ,Janus Kinase 1 ,Cell Biology ,Protein-Tyrosine Kinases ,Cell biology ,DNA-Binding Proteins ,STAT1 Transcription Factor ,Stem cell fate determination ,Trans-Activators ,Drosophila ,Signal transduction ,Signal Transduction - Abstract
In multicellular organisms, biological activities are regulated by cell signaling. The various signal transduction pathways regulate cell fate, proliferation, migration, and polarity. Miscoordination of the communicative signals will lead to disasters like cancer and other fatal diseases. The JAK/STAT signal transduction pathway is one of the pathways, which was first identified in vertebrates and is highly conserved throughout evolution. Studying the JAK/STAT signal transduction pathway in Drosophila provides an excellent opportunity to understand the molecular mechanism of the cell regulation during development and tumor formation. In this review, we discuss the general overview of JAK/STAT signaling in Drosophila with respect to its functions in the eye development and stem cell fate determination.
- Published
- 2005
33. The JAK/STAT Pathway in Model Organisms
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Norbert Perrimon, Steven X. Hou, Xiu Chen, and Zhiyu Zheng
- Subjects
Convergent extension ,ved/biology ,ved/biology.organism_classification_rank.species ,PIM1 ,JAK-STAT signaling pathway ,Cell migration ,Cell Biology ,Cell fate determination ,Biology ,biology.organism_classification ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Signal transduction ,Model organism ,Molecular Biology ,Zebrafish ,Developmental Biology - Abstract
The JAK/STAT pathway was originally identified in mammals. Studies of this pathway in the mouse have revealed that JAK/STAT signaling plays a central role during hematopoeisis and other developmental processes. The role of JAK/STAT signaling in blood appears to be conserved throughout evolution, as it is also required during fly hematopoeisis. Studies in Dictyostelium, Drosophila, and zebrafish have shown that the JAK/STAT pathway is also required in an unusually broad set of developmental decisions, including cell proliferation, cell fate determination, cell migration, planar polarity, convergent extension, and immunity. There is increasing evidence that the versatility of this pathway relies on its cooperation with other signal transduction pathways. In this review, we discuss the components of the JAK/STAT pathway in model organisms and what is known about its requirement in cellular and developmental processes. In particular, we emphasize recent insights into the role that this pathway plays in the control of cell movement.
- Published
- 2002
34. mom identifies a receptor for the Drosophila JAK/STAT signal transduction pathway and encodes a protein distantly related to the mammalian cytokine receptor family
- Author
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Hua-Wei Chen, Xiu Chen, Steven X. Hou, J. Silvio Gutkind, Su-Wan Oh, and Maria Julia Marinissen
- Subjects
Molecular Sequence Data ,Biology ,Transfection ,Genetics ,Animals ,Drosophila Proteins ,Amino Acid Sequence ,Cloning, Molecular ,Receptors, Cytokine ,Transcription factor ,Cells, Cultured ,In Situ Hybridization ,Body Patterning ,Glycoproteins ,Janus Kinases ,Janus kinase 1 ,Membrane Proteins ,Exons ,Janus Kinase 1 ,Protein-Tyrosine Kinases ,biology.organism_classification ,Introns ,Cell biology ,DNA-Binding Proteins ,Trachea ,STAT Transcription Factors ,Drosophila melanogaster ,ComputingMethodologies_PATTERNRECOGNITION ,Trans-Activators ,Insect Proteins ,Female ,Signal transduction ,Cytokine receptor ,Janus kinase ,Drosophila Protein ,Signal Transduction ,Transcription Factors ,Research Paper ,Developmental Biology - Abstract
The JAK/STAT signal transduction pathway controls numerous events inDrosophila melanogaster development. Receptors for the pathway have yet to be identified. Here we have identified a Drosophilagene that shows embryonic mutant phenotypes identical to those in the hopscotch (hop)/JAK kinase and marelle(mrl)/Stat92e mutations. We named this genemaster of marelle (mom). Genetic analyses placemom's function between upd (the ligand) andhop. We further show that cultured cells transfected with themom gene bind UPD and activate the HOP/STAT92E signal transduction pathway. mom encodes a protein distantly related to the mammalian cytokine receptor family. These data show thatmom functions as a receptor of the Drosophila JAK/STAT signal transduction pathway.
- Published
- 2002
35. Kidney Stem Cells Found in Adult Zebrafish
- Author
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Xiankun Zeng and Steven X. Hou
- Subjects
biology ,urogenital system ,Amniotic stem cells ,Anatomy ,Cell Biology ,urologic and male genital diseases ,biology.organism_classification ,Article ,Cell biology ,Endothelial stem cell ,Genetics ,Molecular Medicine ,Progenitor cell ,Stem cell ,Zebrafish ,Renal stem cell ,Stem cell transplantation for articular cartilage repair ,Adult stem cell - Abstract
Loss of kidney function underlies many renal diseases1. Mammals can partly repair their nephrons (the functional units of the kidney), but cannot form new ones2,3. By contrast, fish add nephrons throughout their lifespan and regenerate nephrons de novo after injury4,5, providing a model for understanding how mammalian renal regeneration may be therapeutically activated. Here we trace the source of new nephrons in the adult zebrafish to small cellular aggregates containing nephron progenitors. Transplantation of single aggregates comprising 10–30 cells is sufficient to engraft adults and generate multiple nephrons. Serial transplantation experiments to test self-renewal revealed that nephron progenitors are long-lived and possess significant replicative potential, consistent with stem-cell activity. Transplantation of mixed nephron progenitors tagged with either green or red fluorescent proteins yielded some mosaic nephrons, indicating that multiple nephron progenitors contribute to a single nephron. Consistent with this, live imaging of nephron formation in transparent larvae showed that nephrogenic aggregates form by the coalescence of multiple cells and then differentiate into nephrons. Taken together, these data demonstrate that the zebrafish kidney probably contains self-renewing nephron stem/progenitor cells. The identification of these cells paves the way to isolating or engineering the equivalent cells in mammals and developing novel renal regenerative therapies.
- Published
- 2011
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36. Genome-wide RNAi screen identifies networks involved in intestinal stem cell regulation in Drosophila
- Author
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Lili Han, Xiankun Zeng, Wei Liu, Ying Liu, Yanhui Hu, Shree Ram Singh, Hanhan Liu, Xinhua Lin, Dong Yan, Steven X. Hou, and Ralph A. Neumüller
- Subjects
inorganic chemicals ,Databases, Factual ,Cell Survival ,Cellular differentiation ,Transgene ,Biology ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,Article ,Animals, Genetically Modified ,Neural Stem Cells ,RNA interference ,Animals ,Drosophila Proteins ,Cell Lineage ,Gene Regulatory Networks ,lcsh:QH301-705.5 ,Cell Proliferation ,RNA, Double-Stranded ,Genetics ,Genome ,Cell growth ,Stem Cells ,fungi ,Cell Differentiation ,Receptors, Interleukin ,Intestinal epithelium ,Phenotype ,Neural stem cell ,Cell biology ,Intestines ,STAT Transcription Factors ,Germ Cells ,lcsh:Biology (General) ,Drosophila ,Female ,RNA Interference ,Stem cell - Abstract
SummaryThe intestinal epithelium is the most rapidly self-renewing tissue in adult animals and maintained by intestinal stem cells (ISCs) in both Drosophila and mammals. To comprehensively identify genes and pathways that regulate ISC fates, we performed a genome-wide transgenic RNAi screen in adult Drosophila intestine and identified 405 genes that regulate ISC maintenance and lineage-specific differentiation. By integrating these genes into publicly available interaction databases, we further developed functional networks that regulate ISC self-renewal, ISC proliferation, ISC maintenance of diploid status, ISC survival, ISC-to-enterocyte (EC) lineage differentiation, and ISC-to-enteroendocrine (EE) lineage differentiation. By comparing regulators among ISCs, female germline stem cells, and neural stem cells, we found that factors related to basic stem cell cellular processes are commonly required in all stem cells, and stem-cell-specific, niche-related signals are required only in the unique stem cell type. Our findings provide valuable insights into stem cell maintenance and lineage-specific differentiation.
- Published
- 2014
37. Stem Cells in the Drosophila Digestive System
- Author
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Xiankun Zeng, Steven X. Hou, and Chhavi Chauhan
- Subjects
MAP Kinase Kinase 4 ,Cellular differentiation ,Biology ,digestive system ,Article ,Epigenesis, Genetic ,Animals ,Drosophila Proteins ,Tissue homeostasis ,Cell Proliferation ,Janus Kinases ,Regeneration (biology) ,Stem Cells ,fungi ,Gene Expression Regulation, Developmental ,Foregut ,Hindgut ,Midgut ,Cell Differentiation ,Receptor, Insulin ,Cell biology ,STAT Transcription Factors ,Drosophila melanogaster ,Stem cell ,Digestive System ,Cell Division ,Adult stem cell ,Signal Transduction ,Transcription Factors - Abstract
Adult stem cells maintain tissue homeostasis by continuously replenishing damaged, aged and dead cells in any organism. Five types of region and organ-specific multipotent adult stem cells have been identified in the Drosophila digestive system: intestinal stem cells (ISCs) in the posterior midgut; hindgut intestinal stem cells (HISCs) at the midgut/hindgut junction; renal and nephric stem cells (RNSCs) in the Malpighian Tubules; type I gastric stem cells (GaSCs) at foregut/midgut junction; and type II gastric stem cells (GSSCs) at the middle of the midgut. Despite the fact that each type of stem cell is unique to a particular organ, they share common molecular markers and some regulatory signaling pathways. Due to the simpler tissue structure, ease of performing genetic analysis, and availability of abundant mutants, Drosophila serves as an elegant and powerful model system to study complex stem cell biology. The recent discoveries, particularly in the Drosophila ISC system, have greatly advanced our understanding of stem cell self-renewal, differentiation, and the role of stem cells play in tissue homeostasis/regeneration and adaptive tissue growth.
- Published
- 2013
38. Generation and Staining of Intestinal Stem Cell Lineage in Adult Midgut
- Author
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Madhuri Kango-Singh, Manoj K. Mishra, Steven X. Hou, and Shree Ram Singh
- Subjects
Staining and Labeling ,Stem Cells ,Regeneration (biology) ,fungi ,Midgut ,Enteroendocrine cell ,Anatomy ,Biology ,digestive system ,Intestinal epithelium ,Regenerative medicine ,Article ,Cell biology ,Intestines ,Drosophila melanogaster ,Cell Tracking ,Animals ,Cell Lineage ,Stem cell ,Signal transduction ,Janus kinase - Abstract
Stem cell-mediated tissue repair is a promising approach in regenerative medicine. Intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. Recently, using lineage tracing and molecular marker labeling, intestinal stem cells (ISCs) have been identified in Drosophila adult midgut. ISCs reside at the basement membrane and are multipotent as they produce both enterocytes and enteroendocrine cells. The adult Drosophila midgut provides an excellent in vivo model organ to study ISC behavior during aging, stress, regeneration, and infection. It has been demonstrated that Notch, Janus kinase/signal transducer and activator of transcription, epidermal growth factor receptor/mitogen-activated protein kinase, Hippo, and wingless signaling pathways regulate ISCs proliferation and differentiation. There are plenty of genetic tools and markers developed in recent years in Drosophila stem cell studies. These tools and markers are essential in the precise identification of stem cells as well as manipulation of genes in stem cell regulation. Here, we describe the details of genetic tools, markers, and immunolabeling techniques used in identification and characterization of adult midgut stem cells in Drosophila.
- Published
- 2012
39. The adult Drosophila gastric and stomach organs are maintained by a multipotent stem cell pool at the foregut/midgut junction in the cardia (proventriculus)
- Author
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Zhiyu Zheng, Shree Ram Singh, Steven X. Hou, and Xiankun Zeng
- Subjects
Cellular differentiation ,Wnt1 Protein ,Biology ,digestive system ,Mice ,Gastric glands ,Report ,medicine ,Humans ,Animals ,Drosophila Proteins ,Hedgehog Proteins ,Molecular Biology ,Cell Proliferation ,Janus Kinases ,Stomach ,Stem Cells ,Multipotent Stem Cells ,fungi ,Gene Expression Regulation, Developmental ,Foregut ,Midgut ,Epithelial Cells ,Cell Differentiation ,Cell Biology ,Anatomy ,Hedgehog signaling pathway ,digestive system diseases ,Cell biology ,Gastrointestinal Tract ,STAT Transcription Factors ,medicine.anatomical_structure ,Drosophila melanogaster ,Bromodeoxyuridine ,Microscopy, Fluorescence ,Multipotent Stem Cell ,Gastric Mucosa ,Cell Transdifferentiation ,Drosophila ,Stem cell ,Developmental Biology ,Signal Transduction ,Transcription Factors - Abstract
Stomach cancer is the second most frequent cause of cancer-related death worldwide. Thus, it is important to elucidate the properties of gastric stem cells, including their regulation and transformation. To date, such stem cells have not been identified in Drosophila. Here, using clonal analysis and molecular marker labeling, we identify a multipotent stem-cell pool at the foregut/midgut junction in the cardia (proventriculus). We found that daughter cells migrate upward either to anterior midgut or downward to esophagus and crop. The cardia functions as a gastric valve and the anterior midgut and crop together function as a stomach in Drosophila; therefore, we named the foregut/midgut stem cells as gastric stem cells (GaSC). We further found that JAK-STAT signaling regulates GaSCs' proliferation, Wingless signaling regulates GaSCs' self-renewal, and hedgehog signaling regulates GaSCs' differentiation. The differentiation pattern and genetic control of the Drosophila GaSCs suggest the possible similarity to mouse gastric stem cells. The identification of the multipotent stem cell pool in the gastric gland in Drosophila will facilitate studies of gastric stem cell regulation and transformation in mammal.
- Published
- 2011
40. Spermatogonial stem cells, infertility and testicular cancer
- Author
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Shree Ram Singh, Steven X. Hou, Ozanna Burnicka-Turek, and Chhavi Chauhan
- Subjects
Infertility ,Male ,endocrine system ,Sterility ,Cellular differentiation ,SSC plasticity ,Reviews ,Biology ,Models, Biological ,spermatogonial stem cell ,Male infertility ,Andrology ,Testicular Neoplasms ,medicine ,Animals ,Humans ,SSC culture ,Testicular cancer ,Infertility, Male ,Cell Proliferation ,Stem Cells ,Cell Differentiation ,Cell Biology ,medicine.disease ,SSC transplantation ,Embryonic stem cell ,Spermatogonia ,testicular cancer ,medicine.anatomical_structure ,Cancer research ,Molecular Medicine ,Stem cell ,infertility ,Germ cell - Abstract
The spermatogonial stem cells (SSCs) are responsible for the transmission of genetic information from an individual to the next generation. SSCs play critical roles in understanding the basic reproductive biology of gametes and treatments of human infertility. SSCs not only maintain normal spermatogenesis, but also sustain fertility by critically balancing both SSC self-renewal and differentiation. This self-renewal and differentiation in turn is tightly regulated by a combination of intrinsic gene expression within the SSC as well as the extrinsic gene signals from the niche. Increased SSCs self-renewal at the expense of differentiation result in germ cell tumours, on the other hand, higher differentiation at the expense of self-renewal can result in male sterility. Testicular germ cell cancers are the most frequent cancers among young men in industrialized countries. However, understanding the pathogenesis of testis cancer has been difficult because it is formed during foetal development. Recent studies suggest that SSCs can be reprogrammed to become embryonic stem (ES)-like cells to acquire pluripotency. In the present review, we summarize the recent developments in SSCs biology and role of SSC in testicular cancer. We believe that studying the biology of SSCs will not only provide better understanding of stem cell regulation in the testis, but eventually will also be a novel target for male infertility and testicular cancers.
- Published
- 2010
41. Intestinal stem cell asymmetric division in the Drosophila posterior midgut
- Author
-
Steven X. Hou
- Subjects
Cell division ,Physiology ,Cellular differentiation ,Clinical Biochemistry ,Wnt1 Protein ,Animals ,Drosophila Proteins ,Cell Proliferation ,biology ,Cell growth ,Stem Cells ,fungi ,Midgut ,Cell Differentiation ,Cell Biology ,Janus Kinase 1 ,biology.organism_classification ,Cell biology ,Intestines ,STAT Transcription Factors ,Drosophila melanogaster ,Stem cell ,Signal transduction ,Drosophila Protein ,Cell Division ,Signal Transduction - Abstract
Over the past 2 years, our understanding of intestinal stem cells in the Drosophila posterior midgut has advanced greatly. In this review, I will focus on the establishment of these stem cells in their niche during development and the molecular mechanisms that regulate their asymmetric division in adults.
- Published
- 2010
42. Competitiveness for the Niche and Mutual Dependence of the Germline and Somatic Stem Cells in the Drosophila Testis Are Regulated by the JAK/STAT Signaling
- Author
-
Su-Wan Oh, Xiu Chen, Shree Ram Singh, Zhiyu Zheng, Hong Wang, and Steven X. Hou
- Subjects
Male ,Cell signaling ,endocrine system ,Physiology ,Somatic cell ,Cellular differentiation ,Clinical Biochemistry ,Suppressor of Cytokine Signaling Proteins ,Cell Communication ,Biology ,Article ,Testis ,Animals ,Drosophila Proteins ,Stem Cell Niche ,Spermatogenesis ,STAT4 ,Germ-Line Mutation ,Janus Kinases ,Stem Cells ,fungi ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Cell Biology ,Cell biology ,STAT Transcription Factors ,Drosophila melanogaster ,Germ Cells ,STAT protein ,Stem cell ,Janus kinase ,Adult stem cell ,Signal Transduction ,Transcription Factors - Abstract
In many tissues, two or more types of stem cells share a niche, and how the stem cells coordinate their self-renewal and differentiation is poorly understood. In the Drosophila testis, germ line stem cells (GSCs) and somatic cyst progenitor cells (CPCs) contact each other and share a niche (the hub). The hub expresses a growth factor unpaired (Upd) that activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in GSCs to regulate the stem cell self-renewal. Here, we demonstrate that the JAK/STAT signaling also regulates CPCs self-renewal. We also show that a negative regulator, the suppressor of cytokine signaling 36E (SOCS36E), suppresses JAK/STAT signaling in somatic cells, preventing them from out-competing the GSCs. Furthermore, through selectively manipulating the JAK/STAT signaling level in either CPCs or GSCs, we demonstrate that the somatic JAK/STAT signaling is essential for self-renewal and maintenance of both CPCs and GSCs. These data suggest that a single JAK/STAT signal from the niche orchestrate the competitive and dependent co-existence of GSCs and CPCs in the Drosophila testis niche.
- Published
- 2010
43. JAK-STAT is restrained by Notch to control cell proliferation of theDrosophilaintestinal stem cells
- Author
-
Shree Ram Singh, Wei Liu, and Steven X. Hou
- Subjects
inorganic chemicals ,Transcription, Genetic ,Notch signaling pathway ,Biology ,digestive system ,Biochemistry ,Article ,Transcriptional regulation ,Animals ,Drosophila Proteins ,Molecular Biology ,Cell Proliferation ,Janus Kinases ,Receptors, Notch ,Cell growth ,Stem Cells ,Regeneration (biology) ,fungi ,JAK-STAT signaling pathway ,Cell Biology ,Cell biology ,Intestines ,STAT Transcription Factors ,Drosophila melanogaster ,Stem cell ,Signal transduction ,Drosophila Protein ,Signal Transduction - Abstract
The Drosophila midgut epithelium undergoes continuous regeneration that is sustained by multipotent intestinal stem cells (ISCs) underneath. Notch signaling has dual functions to control ISC behavior: it slows down the ISC proliferation and drives the activated ISCs into different differentiation pathways at a dose-dependent manner. Here we identified a molecular mechanism to unite these two contradictory functions. We found JAK-STAT signaling controls ISC proliferation and this ability is negatively regulated by Notch at least through a transcriptional control of the JAK-STAT signaling ligand, unpaired (upd). This study provides insight into how stem cells, under steady conditions, balance the processes of proliferation and differentiation to maintain the stable cellular composition of a healthy tissue.
- Published
- 2010
44. Regulation of intestinal stem cells in mammals and Drosophila
- Author
-
Steven X. Hou and Ping Wang
- Subjects
Mammals ,Physiology ,Cellular differentiation ,Stem Cells ,fungi ,Clinical Biochemistry ,Cell ,Notch signaling pathway ,Mouse Small Intestine ,Midgut ,Cell Biology ,Biology ,Intestinal epithelium ,Cell biology ,medicine.anatomical_structure ,Drosophila melanogaster ,medicine ,Animals ,Stem cell ,Intestinal Mucosa ,Adult stem cell ,Cell Proliferation ,Signal Transduction - Abstract
The digestive systems in mammals and Drosophila are quite different in terms of their complexity and organization, but their biological functions are similar. The Drosophila midgut is a functional equivalent of the mouse small intestine. Adult intestinal stem cells (ISCs) have been identified in both the mouse small intestine and Drosophila midgut. The anatomy and cell renewal in the Drosophila midgut are similar to those in the mouse small intestine: the intestinal epithelium in both systems is a tube composed of epithelial cells with absorptive and secretory functions; the Notch signaling controls absorptive versus secretory fate decisions in the intestinal epithelium; cell renewal in both systems starts from stem cells in the basal cell layer, and the differentiated cells then move toward the lumen. However, it is clear that the stem cells in the two systems are regulated in different ways. In this review, we will compare cell renewal and stem cell regulation in the two systems.
- Published
- 2009
45. Genetic tools used for cell lineage tracing and gene manipulation in Drosophila germline stem cells
- Author
-
Wei, Liu and Steven X, Hou
- Subjects
Male ,Saccharomyces cerevisiae Proteins ,Mosaicism ,Green Fluorescent Proteins ,Recombinant Proteins ,Animals, Genetically Modified ,Repressor Proteins ,Adult Stem Cells ,Germ Cells ,Genetic Techniques ,Lac Operon ,Tubulin ,Mutation ,Animals ,Drosophila ,Female - Abstract
The advancement of Drosophila germline stem cell research accompanies the development of powerful new tools for genetic analysis. These include the techniques of stem cell labeling, cell lineage tracing, mosaic mutant analysis, and gene manipulation in targeted cell populations, which together constitute the critical methodologies in stem cell research. We discuss four such techniques: the tubulin-lacZ positive-labeling system; the positively marked mosaic lineage (PMML) method; the flipase/flipase recombination target (FLP/FRT)-based mosaic mutant analysis; and the GAL80-based mosaic analysis with a repressible cell marker (MARCM) system.
- Published
- 2008
46. Immunohistological techniques for studying the Drosophila male germline stem cell
- Author
-
Shree Ram, Singh and Steven X, Hou
- Subjects
Male ,Adult Stem Cells ,MAP Kinase Signaling System ,Histological Techniques ,Animals ,Drosophila ,Spermatogenesis ,Immunohistochemistry ,Spermatozoa ,Signal Transduction - Abstract
Stem cells are undifferentiated cells that have a remarkable ability to self-renew and produce differentiated cells that support normal development and tissue homeostasis. This unique capacity makes stem cells a powerful tool for future regenerative medicine and gene therapy. Accumulative evidence suggests that stem cell self-renewal or differentiation is controlled by both intrinsic and extrinsic factors, and that deregulation of stem cell behavior results in cancer formation, tissue degeneration, and premature aging. The Drosophila testis provides an excellent in vivo model for studying and understanding the fundamental cellular and molecular mechanisms controlling stem cell behavior and the relationship between niches and stem cells. At the tip of the Drosophila testes, germline stem cells (GSCs) and somatic stem cells (SSCs) contact each other and share common niches (known as a hub) to maintain spermatogenesis. Signaling pathways, such as the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), bone morphogenetic protein (BMP), ras-associated protein-guanine nucleotide exchange factor for small GTPase (Rap-GEF), and epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK), are known to regulate self-renewal or differentiation of Drosophila male germline stem cells. We describe the detailed in vivo immunohistological protocols that mark GSCs, SSCs, and their progeny in Drosophila testes.
- Published
- 2008
47. Immunohistological Techniques for Studying the Drosophila Male Germline Stem Cell
- Author
-
Steven X. Hou and Shree Ram Singh
- Subjects
Genetics ,Premature aging ,Cellular differentiation ,Biology ,Stem cell ,Bone morphogenetic protein ,Regenerative medicine ,Germline ,Tissue homeostasis ,Cell biology ,Adult stem cell - Abstract
Stem cells are undifferentiated cells that have a remarkable ability to self-renew and produce differentiated cells that support normal development and tissue homeostasis. This unique capacity makes stem cells a powerful tool for future regenerative medicine and gene therapy. Accumulative evidence suggests that stem cell self-renewal or differentiation is controlled by both intrinsic and extrinsic factors, and that deregulation of stem cell behavior results in cancer formation, tissue degeneration, and premature aging. The Drosophila testis provides an excellent in vivo model for studying and understanding the fundamental cellular and molecular mechanisms controlling stem cell behavior and the relationship between niches and stem cells. At the tip of the Drosophila testes, germline stem cells (GSCs) and somatic stem cells (SSCs) contact each other and share common niches (known as a hub) to maintain spermatogenesis. Signaling pathways, such as the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), bone morphogenetic protein (BMP), ras-associated protein-guanine nucleotide exchange factor for small GTPase (Rap-GEF), and epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK), are known to regulate self-renewal or differentiation of Drosophila male germline stem cells. We describe the detailed in vivo immunohistological protocols that mark GSCs, SSCs, and their progeny in Drosophila testes.
- Published
- 2008
48. Genetic Tools Used for Cell Lineage Tracing and Gene Manipulation in Drosophila Germline Stem Cells
- Author
-
Steven X. Hou and Wei Liu
- Subjects
Genetics ,Mutation ,Lineage (genetic) ,MARCM ,Mutant ,medicine ,Computational biology ,Biology ,Stem cell ,medicine.disease_cause ,Germline ,Stem cell lineage database ,Adult stem cell - Abstract
The advancement of Drosophila germline stem cell research accompanies the development of powerful new tools for genetic analysis. These include the techniques of stem cell labeling, cell lineage tracing, mosaic mutant analysis, and gene manipulation in targeted cell populations, which together constitute the critical methodologies in stem cell research. We discuss four such techniques: the tubulin-lacZ positive-labeling system; the positively marked mosaic lineage (PMML) method; the flipase/flipase recombination target (FLP/FRT)-based mosaic mutant analysis; and the GAL80-based mosaic analysis with a repressible cell marker (MARCM) system.
- Published
- 2008
49. Germline Stem Cells
- Author
-
Shree Ram Singh and Steven X. Hou
- Subjects
Transplantation ,ved/biology ,Male fertility ,ved/biology.organism_classification_rank.species ,Epigenetics ,Cell lineage ,Stem cell ,Biology ,Model organism ,Gene ,Germline ,Cell biology - Abstract
Contents Preface... Contributors... Part I Identification and Regulation of Germline Stem Cells in Model Organisms The Development of Germline Stem Cells in Drosophila David A. Dansereau and Paul Lasko... Analysis of the C. elegans Germline Stem Cell Region Sarah L. Crittenden and Judith Kimble ... Immunohistological Techniques for Studying the Drosophila Male Germline Stem Cell Shree Ram Singh and Steven X. Hou... Genetic Tools Used for Cell Lineage Tracing and Gene Manipulation in Drosophila Germline Stem Cells Wei Liu and Steven X. Hou... Structural Polarity and Dynamics of Male Germline Stem Cells in an Insect (the milkweed bug Oncopeltus fasciatus) David C. Dorn and August Dorn... High Resolution Light Microscopic Characterization of Spermatogonia Helio Chiarini-Garcia and Marvin L Meistrich... Identification and Characterization of Spermatogonial Subtypes and Their Expansion in Whole Mounts and Tissue Sections from Primate Testes Jens Ehmcke and Stefan Schlatt... Epigenetic Control in Male Germ Cells Durga Prasad Mishra and PaoloSassone-Corsi... GDNF Maintains Mouse Spermatogonial Stem Cells in vivo and in vitro Hannu Sariola and Tiina Immonen... Part II In vitro Culture and Applications of Germline Stem Cells Ectopic Grafting of Mammalian Testis Tissue into Mouse Hosts Ina Dobrinski and Rahul Rathi... Spermatogonial Stem Cell Transplantation, Testicular Function and Restoration of Male Fertility in Mice Derek J. McLean... 12 Isolating Highly Pure Rat Spermatogonial Stem Cells in Culture F. Kent Hamra, Karen M. Chapman, Zhuoru Wu, and David L. Garbers...chrically Complex Trait Jason D. Heaney and Joseph H. Nadeau... Study Origin of Germ Cells and Formation of New Primary Follicles in Adult Human and Rat Ovaries Antonin Bukovsky, Satish K. Gupta, Irma Virant-Klun, Nirmala B. Upadhyaya, Pleas Copas, Stuart E. Van Meter, Marta Svetlikova, Maria E. Ayala, and Roberto Dominguez ... Index...
- Published
- 2008
50. A P-element insertion screen identified mutations in 455 novel essential genes in Drosophila
- Author
-
Peizheng Ruan, Hua-Wei Chen, Xiu Chen, Hyun-hee Shin, Zhiyu Zheng, Hong Wang, Tracy Kingsley, Michelle Moody, Steven X. Hou, and Su-Wan Oh
- Subjects
TBX1 ,Genetics ,Mutation ,Chimeric gene ,Biology ,medicine.disease_cause ,Genome ,Chromosome 15 ,medicine ,DNA Transposable Elements ,Animals ,Minimal genome ,Drosophila ,Genes, Lethal ,Chromosome 22 ,Gene ,Research Article - Abstract
With the completion of the nucleotide sequences of several complex eukaryotic genomes, tens of thousands of genes have been predicted. However, this information has to be correlated with the functions of those genes to enhance our understanding of biology and to improve human health care. The Drosophila transposon P-element-induced mutations are very useful for directly connecting gene products to their biological function. We designed an efficient transposon P-element-mediated gene disruption procedure and performed genetic screening for single P-element insertion mutations, enabling us to recover 2500 lethal mutations. Among these, 2355 are second chromosome mutations. Sequences flanking >2300 insertions that identify 850 different genes or ESTs (783 genes on the second chromosome and 67 genes on the third chromosome) have been determined. Among these, 455 correspond to genes for which no lethal mutation has yet been reported. The Drosophila genome is thought to contain ∼3600 vital genes; 1400 are localized on the second chromosome. Our mutation collection represents ∼56% of the second chromosome vital genes and ∼24% of the total vital Drosophila genes.
- Published
- 2003
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