29 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
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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.
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- 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 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.
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- 2015
25. 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
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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.
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- 2015
26. Arf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice
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Guohao Wang, Junji Xu, Jiangsha Zhao, Weiqin Yin, Dayong Liu, WanJun Chen, and Steven X. Hou
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Science - Abstract
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
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27. Whole-animal genome-wide RNAi screen identifies networks regulating male germline stem cells in Drosophila
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Ying Liu, Qinglan Ge, Brian Chan, Hanhan Liu, Shree Ram Singh, Jacob Manley, Jae Lee, Ann Marie Weideman, Gerald Hou, and Steven X. Hou
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Science - Abstract
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.
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- 2016
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28. The novel tumour suppressor Madm regulates stem cell competition in the Drosophila testis
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Shree Ram Singh, Ying Liu, Jiangsha Zhao, Xiankun Zeng, and Steven X. Hou
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Science - Abstract
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.
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- 2016
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29. Genome-wide RNAi Screen Identifies Networks Involved in Intestinal Stem Cell Regulation in Drosophila
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Xiankun Zeng, Lili Han, Shree Ram Singh, Hanhan Liu, Ralph A. Neumüller, Dong Yan, Yanhui Hu, Ying Liu, Wei Liu, Xinhua Lin, and Steven X. Hou
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Biology (General) ,QH301-705.5 - Abstract
The 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.
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- 2015
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