16 results on '"Wai-Chi Ho"'
Search Results
2. Transcellular blood–brain barrier disruption in malaria-induced reversible brain edema
- Author
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Jin, Jessica, primary, Ba, Mame Aida, additional, Wai, Chi Ho, additional, Mohanty, Sanjib, additional, Sahu, Praveen K, additional, Pattnaik, Rajyabardhan, additional, Pirpamer, Lukas, additional, Fischer, Manuel, additional, Heiland, Sabine, additional, Lanzer, Michael, additional, Frischknecht, Friedrich, additional, Mueller, Ann-Kristin, additional, Pfeil, Johannes, additional, Majhi, Megharay, additional, Cyrklaff, Marek, additional, Wassmer, Samuel C, additional, Bendszus, Martin, additional, and Hoffmann, Angelika, additional
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- 2022
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3. Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages
- Author
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Jin, Jessica, primary, Ba, Mame Aida, additional, Wai, Chi Ho, additional, Mohanty, Sanjib, additional, Sahu, Praveen K., additional, Pattnaik, Rajyabardham, additional, Pirpamer, Lukas, additional, Fischer, Manuel, additional, Heiland, Sabine, additional, Lanzer, Michael, additional, Frischknecht, Friedrich, additional, Mueller, Ann-Kristin, additional, Pfeil, Johannes, additional, Majhi, Megharay, additional, Cyrklaff, Marek, additional, Wassmer, Samuel C., additional, Bendszus, Martin, additional, and Hoffmann, Angelika, additional
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- 2021
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4. Calpain 2 Regulates Akt-FoxO-p27Kip1 Protein Signaling Pathway in Mammary Carcinoma
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Larissa Pikor, Peter A. Greer, Bruce E. Elliott, Yan Gao, and Wai-chi Ho
- Subjects
Cytoplasm ,Lung Neoplasms ,Tumor suppressor gene ,Blotting, Western ,Mice, Nude ,Mammary Neoplasms, Animal ,medicine.disease_cause ,Biochemistry ,Mice ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Molecular Biology ,Protein kinase B ,Cell Proliferation ,Cell Nucleus ,Gene knockdown ,biology ,Calpain ,Cell growth ,Forkhead Box Protein O3 ,Forkhead Transcription Factors ,Cell Biology ,Protein phosphatase 2 ,Tumor Burden ,Cell biology ,Microscopy, Fluorescence ,biology.protein ,Cancer research ,Female ,RNA Interference ,Signal transduction ,Carcinogenesis ,Proto-Oncogene Proteins c-akt ,Cyclin-Dependent Kinase Inhibitor p27 ,Signal Transduction - Abstract
We investigated the role of the ubiquitously expressed calpain 2 isoform in breast tumor cell growth, migration, signaling, and tumorigenesis. RNAi-mediated knockdown of the capn2 transcript was used to manipulate expression of the catalytic subunit of calpain 2 in the AC2M2 mouse mammary carcinoma cell line. Stable knockdown of capn2 correlated with reduced in vitro proliferation rates, soft agar colony formation efficiency, and migration rates, indicating roles for calpain 2 in mitogenesis, survival, and motogenesis. Biochemical analysis showed increased levels of protein phosphatase 2A and reduced levels of activated Akt in calpain 2-deficient cells, and this correlated with increased levels of the FoxO3a target gene product p27(Kip1), a key regulator of cell proliferation. Calpain 2 deficiency in the AC2M2 cells correlated with enhanced nuclear localization of FoxO3a, consistent with it being in a derepressed state capable of regulating transcriptional targets. Orthotopically engrafted calpain 2 knockdown AC2M2 cells generated tumors with reduced growth rates and enhanced in vivo expression of p27(Kip1). In summary, calpain 2 deficiency correlated with reduced Akt activity, increased protein phosphatase 2A levels, derepression of FoxO3a, and enhanced expression of the p27(Kip1) tumor suppressor. These observations argue that calpain 2 promotes tumor cell growth both in vitro and in vivo through the PI3K-Akt-FoxO-p27(Kip1) signaling cascade. Inhibition of calpain 2 might therefore provide therapeutic benefits in the treatment of cancer.
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- 2012
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5. cIAP1 and cIAP2 Facilitate Cancer Cell Survival by Functioning as E3 Ligases that Promote RIP1 Ubiquitination
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Wai Chi Ho, Alain Boudreault, Snezana Milutinovic, Kathleen M. Dickson, Philip A. Barker, John W. Gillard, James B. Jaquith, Stephen Morris, Jon P. Durkin, and Mathieu J.M. Bertrand
- Subjects
Cell Survival ,Ubiquitin-Protein Ligases ,Ripoptosome ,Inhibitor of apoptosis ,Inhibitor of Apoptosis Proteins ,03 medical and health sciences ,RIPK1 ,0302 clinical medicine ,Ubiquitin ,Cell Line, Tumor ,Baculoviral IAP Repeat-Containing 3 Protein ,Humans ,Molecular Biology ,030304 developmental biology ,Ovarian Neoplasms ,0303 health sciences ,Caspase 8 ,Sulfonamides ,biology ,Cell Death ,Kinase ,Signal transducing adaptor protein ,RNA-Binding Proteins ,Cell Biology ,3. Good health ,Cell biology ,Enzyme Activation ,Nuclear Pore Complex Proteins ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Female - Abstract
Summary The inhibitor of apoptosis (IAP) family of proteins enhances cell survival through mechanisms that remain uncertain. In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. When deubiquitinated by AEG40730 treatment, RIP1 binds caspase-8 and induces apoptosis. These findings provide insights into the function of the IAPs and provide new therapeutic opportunities in the treatment of cancer.
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- 2008
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6. AEG3482 Is an Antiapoptotic Compound that Inhibits Jun Kinase Activity and Cell Death through Induced Expression of Heat Shock Protein 70
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Amir H. Salehi, Kathleen M. Dickson, Stephen J. Morris, Jon P. Durkin, Wai-Chi Ho, John W. Gillard, Snezana Milutinovic, Genevieve Doucet, and Philip A. Barker
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Programmed cell death ,Lactams, Macrocyclic ,Clinical Biochemistry ,Apoptosis ,CELLCYCLE ,PC12 Cells ,Receptor, Nerve Growth Factor ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Antigens, Neoplasm ,Thiadiazoles ,Drug Discovery ,Benzoquinones ,Low-affinity nerve growth factor receptor ,Animals ,HSP70 Heat-Shock Proteins ,Enzyme Inhibitors ,Phosphorylation ,Molecular Biology ,030304 developmental biology ,Neurons ,Pharmacology ,0303 health sciences ,Sulfonamides ,biology ,JUN kinase activity ,JNK Mitogen-Activated Protein Kinases ,Quinones ,General Medicine ,JUN kinase ,Cell cycle ,Hsp90 ,Cell biology ,Hsp70 ,Neoplasm Proteins ,Rats ,Enzyme Activation ,CHEMBIO ,SIGNALING ,biology.protein ,Cancer research ,Molecular Medicine ,030217 neurology & neurosurgery - Abstract
SummaryWe describe a group of small-molecule inhibitors of Jun kinase (JNK)-dependent apoptosis. AEG3482, the parental compound, was identified in a screening effort designed to detect compounds that reduce apoptosis of neonatal sympathetic neurons after NGF withdrawal. We show that AEG3482 blocks apoptosis induced by the p75 neurotrophin receptor (p75NTR) or its cytosolic interactor, NRAGE, and demonstrate that AEG3482 blocks proapoptotic JNK activity. We show that AEG3482 induces production of heat shock protein 70 (HSP70), an endogenous inhibitor of JNK, and establish that HSP70 accumulation is required for the AEG3482-induced JNK blockade. We show that AEG3482 binds HSP90 and induces HSF1-dependent HSP70 mRNA expression and find that AEG3482 facilitates HSP70 production while retaining HSP90 chaperone activity. These studies establish that AEG3482 inhibits JNK activation and apoptosis by a mechanism involving induced expression of HSP proteins.
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- 2006
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7. A Differential Role of Extracellular Signal-Regulated Kinase in Stimulated PC12 Pheochromocytoma Cell Movement
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Bosco M.C. Chan, Vincent L. Morris, Susan O. Meakin, Shashi Uniyal, and Wai-chi Ho
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MAPK/ERK pathway ,MAP Kinase Signaling System ,Immunoblotting ,Integrin ,Chemokinesis ,Biology ,PC12 Cells ,Cell Movement ,Epidermal growth factor ,Nerve Growth Factor ,Neurites ,Extracellular ,Animals ,Enzyme Inhibitors ,Phosphorylation ,Flavonoids ,Epidermal Growth Factor ,Kinase ,Chemotaxis ,Cell Biology ,Precipitin Tests ,Rats ,Cell biology ,Enzyme Activation ,Nerve growth factor ,nervous system ,biology.protein ,Mitogen-Activated Protein Kinases - Abstract
Rat pheochromocytoma PC12 cells have been widely used as a cell system for study of growth factor-stimulated cell functions. We report here that nerve growth factor (NGF) stimulated both chemotaxis (directional migration) and chemokinesis (random migration) of PC12 cells. Treatment with a MEK1/2-specific inhibitor (PD98059) or expression of a dominant negative variant of Ras differentially inhibited NGF-stimulated chemotaxis but not chemokinesis of PC12 cells. Priming of PC12 cells with NGF resulted in reduced extracellular signal-regulated kinase (ERK) activation and loss of chemotactic, but not chemokinetic, response. In addition, NGF stimulation of ERK is known to involve an early transient phase of activation followed by a late sustained phase of activation; in contrast, epidermal growth factor (EGF) elicits only early transient ERK activation. We observed that like NGF, EGF also stimulated both chemotaxis and chemokinesis, and treatment with PD98059 abolished the EGF-stimulated chemotaxis. Therefore, the early transient phase of ERK activation functioned in signaling chemotaxis; the late sustained phase of ERK activation did not seem to have an essential role. In addition, our results suggested that chemotactic signaling required a threshold level of ERK activation; at below threshold level of ERK activation, chemotaxis would not occur.
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- 2001
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8. Differences in phosphatase modulation of α4 β1 and α5 β1 integrin-mediated adhesion and migration of B16F1 cells
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Bosco M.C. Chan, Dolores Hangan-Steinman, Vincent L. Morris, Priti S Shenoy, and Wai-chi Ho
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biology ,Phosphatase ,Integrin ,Cell migration ,Cell Biology ,Protein tyrosine phosphatase ,Okadaic acid ,Biochemistry ,Cell biology ,Fibronectin ,chemistry.chemical_compound ,chemistry ,biology.protein ,Signal transduction ,Cell adhesion ,Molecular Biology - Abstract
It is well established that a biphasic relationship exists between the adhesive strength of β1 integrins and their ability to mediate cell movement. Thus, cell movement increases progressively with adhesive strength, but beyond a certain point of optimal interaction, cell movement is reduced with further increases in adhesive function. The interplay between the various kinase and phosphatase activities provides the balance in β1 integrin-mediated cell adhesion and migration. In the present study, the significance of protein tyrosine phosphatases (PTP) and ser/thr protein phosphatases (PP) in α4β1 and α5β1 integrin-mediated mouse melanoma B16F1 cell anchorage and migration on fibronectin was characterized using phosphatase inhibitors. At low fibronectin concentration, α5β1 functioned as the predominant receptor for cell movement; a role for α4β1 in B16F1 cell migration increased progressively with fibronectin concentration. Treatment of B16F1 cells with PTP inhibitors, sodium orthovanadate (Na3VO4) and phenylarsine oxide (PAO), or PP-1/2A inhibitor, okadaic acid (OA), abolished cell movement. Inhibition of cell movement by PAO and OA was associated by a reduction in the adhesive strength of α4β1 and α5β1. In contrast, treatment of B16F1 cells with Na3VO4 resulted in selective stimulation of the adhesive function of α5β1, but not α4β1. Therefore, our results demonstrate that (i) both PTP and PP-1/2A have roles in cell movement, (ii) modulation of cell movement by PTP and PP-1/2A may involve either a stimulation or reduction of β1 integrin adhesive strength, and (iii) distinct phosphatase-mediated signaling pathways for differential regulation of the various β1 integrins exist. Key words: phosphatases, integrins, cell movement, cell adhesion.
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- 1999
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9. Fu Wei-Lin (?-1667) and his Ming-Shu = Fu Weilin (?-1667) ji qi 'Ming shu'
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Wai-chi. Ho
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- 2012
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10. Eunuch politics in early Ming dynasty = Ming chu zhi huan guan zheng zhi
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Wai-chi. Ho
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Politics ,History ,Ancient history - Published
- 2012
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11. Hypo-osmolar stress induces p75NTR expression by activating Sp1-dependent transcription
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Wai Chi Ho, Stephanie Forte, Philip A. Barker, Kristy Favell, Kathleen M. Dickson, Jacqueline Boutilier, and Alberto Javier Ramos
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Transcription, Genetic ,Endogeny ,Electrophoretic Mobility Shift Assay ,Kidney ,Mice ,Phosphatidylinositol 3-Kinases ,Transcription (biology) ,Gene expression ,Low-affinity nerve growth factor receptor ,Cycloheximide ,RNA, Small Interfering ,Promoter Regions, Genetic ,Protein Kinase C ,Genes, Dominant ,Phosphoinositide-3 Kinase Inhibitors ,Cerebral Cortex ,Neurons ,General Neuroscience ,Articles ,Sp3 Transcription Factor ,Hypotonic Solutions ,Neurotrophin ,Protein Binding ,Sp1 Transcription Factor ,Recombinant Fusion Proteins ,Nerve Tissue Proteins ,Receptors, Nerve Growth Factor ,Biology ,Cell Line ,Species Specificity ,Osmotic Pressure ,Sequence Homology, Nucleic Acid ,Consensus Sequence ,Animals ,Humans ,Receptors, Growth Factor ,RNA, Messenger ,Gene ,Binding Sites ,Osmotic concentration ,DNA ,Molecular biology ,Rats ,Proteasome ,Gene Expression Regulation ,Type C Phospholipases ,Mutation ,biology.protein ,sense organs ,Protein Processing, Post-Translational - Abstract
Injury-induced expression of the p75 neurotrophin receptor (p75NTR) in the CNS facilitates neuronal apoptosis and prevents neuronal regrowth, but the mechanisms regulating p75NTR expression are poorly characterized. In this study, we showed that hypo-osmolarity induces p75NTR expression in primary neurons, and, using a comparative genomics approach, we identified conserved elements in the 25 kb upstream sequences of the rat, mouse, and human p75NTR genes. We found that only one of these, a proximal region rich in Sp1 sites, responds to changes in hypo-osmolarity. We then showed that Sp1 DNA binding activity is increased in cells exposed to hypo-osmolarity, established that hypo-osmolarity enhanced Sp1 binding to the endogenous p75NTR promoter, and showed that Sp1 is required for p75NTR expression induced by hypo-osmolarity. We examined how Sp1 is regulated to effect these changes and established that Sp1 turnover is strongly inhibited by hypo-osmolarity. We propose that stress-induced Sp1 accumulation that results from reductions in Sp1 turnover rate contributes to injury-induced gene expression.
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- 2007
12. Nuclear factor-kappaB induced by doxorubicin is deficient in phosphorylation and acetylation and represses nuclear factor-kappaB-dependent transcription in cancer cells
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Kathleen M. Dickson, Philip A. Barker, and Wai Chi Ho
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Cancer Research ,Anthracycline ,Transcription, Genetic ,Breast Neoplasms ,Histone Deacetylases ,Transcription (biology) ,Cell Line, Tumor ,medicine ,Humans ,Doxorubicin ,Phosphorylation ,Antibiotics, Antineoplastic ,biology ,NF-kappa B ,Acetylation ,Histone ,Oncology ,Cell culture ,Cancer cell ,biology.protein ,Cancer research ,medicine.drug ,Protein Modification, Translational ,Signal Transduction - Abstract
The primary goal of chemotherapy is to cause cancer cell death. However, a side effect of many commonly used chemotherapeutic drugs is the activation of nuclear factor-κB (NF-κB), a potent inducer of antiapoptotic genes, which may blunt the therapeutic efficacy of these compounds. We have assessed the effect of doxorubicin, an anthracycline in widespread clinical use, on NF-κB activation and expression of antiapoptotic genes in breast cancer cells. We show that doxorubicin treatment activates NF-κB signaling and produces NF-κB complexes that are competent for NF-κB binding in vitro. Surprisingly, these NF-κB complexes suppress, rather than activate, constitutive- and cytokine-induced NF-κB–dependent transcription. We show that doxorubicin treatment produces RelA, which is deficient in phosphorylation and acetylation and which blocks NF-κB signaling in a histone deacetylase–independent manner, and we show that NF-κB activated by doxorubicin does not remain stably bound to κB elements in vivo. Together these data show that NF-κB signaling induced by doxorubicin reduces expression of NF-κB–dependent genes in cancer cells.
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- 2005
13. Modulation of In Vivo Migratory Function of α2β1 Integrin in Mouse Liver
- Author
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Shashi Uniyal, Wai-chi Ho, Christine Heinemann, Dolores Hangan, Vincent L. Morris, and Bosco M.C. Chan
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Cell type ,Liver cytology ,Integrin alpha2 ,Article ,Collagen receptor ,Cell Line ,Mice ,Laminin ,Antigens, CD ,Cell Movement ,Cell Adhesion ,Tumor Cells, Cultured ,Animals ,Humans ,Beta (finance) ,Molecular Biology ,biology ,Integrin beta1 ,Antibodies, Monoclonal ,Cell Biology ,Molecular biology ,Extravasation ,Liver ,Cell culture ,biology.protein ,Collagen - Abstract
We report herein that expression of alpha 2 beta 1 integrin increased human erythroleukemia K562 transfectant (KX2C2) cell movement after extravasation into liver parenchyma. In contrast, a previous study demonstrated that alpha 2 beta 1 expression conferred a stationary phenotype to human rhabdomyosarcoma RD transfectant (RDX2C2) cells after extravasation into the liver. We therefore assessed the adhesive and migratory function of alpha 2 beta 1 on KX2C2 and RDX2C2 cells using a alpha 2 beta 1-specific stimulatory monoclonal antibody (mAb), JBS2, and a blocking mAb, BHA2.1. In comparison with RDX2C2 cells, KX2C2 were only weakly adherent to collagen and laminin. JBS2 stimulated alpha 2 beta 1-mediated interaction of KX2C2 cells with both collagen and laminin resulting in increases in cell movement on both matrix proteins. In the presence of Mn2+, JBS2-stimulated adhesion on collagen beyond an optimal level for cell movement. In comparison, an increase in RDX2C2 cell movement on collagen required a reduction in its adhesive strength provided by the blocking mAb BHA2.1. Consistent with these in vitro findings, in vivo videomicroscopy revealed that alpha 2 beta 1-mediated postextravasation cell movement of KX2C2 cells in the liver tissue could also be stimulated by JBS2. Thus, results demonstrate that alpha 2 beta 1 expression can modulate postextravasation cell movement by conferring either a stationary or motile phenotype to different cell types. These findings may be related to the differing metastatic activities of different tumor cell types.
- Published
- 1997
14. Abstract 3168: Knock down of m-calpain in a mouse breast carcinoma cell line reduced tumor growth in mouse engraftment studies and compromises the Akt pathway and in vitro cell migration
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Wai-chi Ho and Peter A. Greer
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Cancer Research ,Gene knockdown ,Cell migration ,Calpain ,Biology ,Molecular biology ,Cell biology ,Focal adhesion ,Oncology ,Cell culture ,Tumor progression ,biology.protein ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
Calpains are a family of calcium-dependent intracellular cysteine proteases consisting of fourteen members, with µ- and m-calpains (calpain 1 and 2) being ubiquitously expressed. Calpains play crucial roles in a various cellular functions including cell survival, movement and calcium homeostasis. Abnormal expression or activation of calpain is linked to pathological conditions such as neurodegenerative diseases, tumor growth and metastasis, platelet malfunction and muscular dysfunction. Studies have showed that calpain is involved in retraction of focal adhesions at the rear of migrating cells, indicating a major role of calpain in cell movement and cytoskeletal organization. In addition, calpain may be a key component in regulating cell survival and gene expression. We have examined the role of m-calpain in tumor growth. Mouse mammary carcinoma cells AC2M2 were transduced with a lentiviral vector expressing shRNA directed against m-calpain or a control shRNA. A mouse xenograft experiment was then carried out by injecting control cells or m-calpain knockdown cells into the mammary fat pads of nude mice. Preliminary results showed that mice injected with m-calpain knockdown cells grow smaller tumors. In vitro transwell migration assay showed that the m-calpain knockdown cells migrated slower than the control cells. Furthermore, biochemical studies demonstrated that these AC2M2 m-calpain knockdown cells have reduced activation of key the survival mediator Akt, although there was no significant difference in the growth rate between the knockdown and the control cells. Other biochemical studies implicate the transcription factor Foxo, a downstream target of Akt, in mediating the m-calpain-regulated tumor progression through activation of transcription of genes that are important in cell survival such as p27 Kip1 and Bim. In summary, our current data suggests that m-calpain mediates tumor growth through regulation of Akt signaling. This in turn regulates Foxo in the activation of gene transcription during cell survival signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3168.
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- 2010
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15. Calpain 2 Regulates Akt-FoxO-p27Kip1 Protein Signaling Pathway in Mammary Carcinoma.
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Wai-chi Ho, Pikor, Larissa, Yan Gao, Elliott, Bruce E., and Greer, Peter A.
- Subjects
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CALPAIN regulation , *BREAST cancer , *CARCINOGENESIS , *CELL migration , *CELL lines , *CELL proliferation , *PHOSPHOPROTEIN phosphatases - Abstract
We investigated the role of the ubiquitously expressed calpain 2 isoform in breast tumor cell growth, migration, signaling, and tumorigenesis. RNAi-mediated knockdown of the capn2 transcript was used to manipulate expression of the catalytic subunit of calpain 2 in the AC2M2 mouse mammary carcinoma cell line. Stable knockdown of capn2 correlated with reduced in vitro proliferation rates, soft agar colony formation efficiency, and migration rates, indicating roles for calpain 2 in mitogenesis, survival, and motogenesis. Biochemical analysis showed increased levels of protein phosphatase 2A and reduced levels of activated Akt in calpain 2-deficient cells, and this correlated with increased levels of the FoxO3a target gene product p27Kip1, a key regulator of cell proliferation. Calpain 2 deficiency in the AC2M2 cells correlated with enhanced nuclear localization of FoxO3a, consistent with it being in a derepressed state capable of regulating transcriptional targets. Orthotopically engrafted calpain 2 knockdown AC2M2 cells generated tumors with reduced growth rates and enhanced in vivo expression of p27Kip1. In summary, calpain 2 deficiency correlated with reduced Akt activity, increased protein phosphatase2Alevels, derepression of FoxO3a, and enhanced expression of the p27Kip1 tumor suppressor. These observations argue that calpain 2 promotes tumor cell growth both in vitro and in vivo through the PI3K-Akt-FoxO-p27Kip1 signaling cascade. Inhibition of calpain 2 might therefore provide therapeutic benefits in the treatment of cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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16. Hypo-Osmolar Stress Induces p75NTR Expression by Activating Sp1-Dependent Transcription.
- Author
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Ramos, Alberto, Wai Chi Ho, Forte, Stephanie, Dickson, Kathleen, Boutilier, Jacqueline, Favell, Kristy, and Barker, Philip A.
- Subjects
- *
NEURAL receptors , *APOPTOSIS , *NEURONS , *GENOMICS , *GENE expression - Abstract
Injury-induced expression of the p75 neurotrophin receptor (p75NTR) in the CNS facilitates neuronal apoptosis and prevents neuronal regrowth, but the mechanisms regulating p75NTR expression are poorly characterized. In this study, we showed that hypo-osmolarity induces p75NTR expression in primary neurons, and, using a comparative genomics approach, we identified conserved elements in the 25 kb upstream sequences of the rat, mouse, and human p75NTR genes. We found that only one of these, a proximal region rich in Sp1 sites, responds to changes in hypo-osmolarity. We then showed that Sp1 DNA binding activity is increased in cells exposed to hypo-osmolarity, established that hypo-osmolarity enhanced Sp1 binding to the endogenous p75NTR promoter, and showed that Sp1 is required for p75NTR expression induced by hypo-osmolarity. We examined how Sp1 is regulated to effect these changes and established that Sp1 turnover is strongly inhibited by hypo-osmolarity. We propose that stress-induced Sp1 accumulation that results from reductions in Sp1 turnover rate contributes to injury-induced gene expression. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
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