Differentiation state-selective roles of p38 isoforms in human intestinal epithelial cell anoikis

Vachon, Pierre H.; Harnois, Charlène; Grenier, Amélie; Dufour, Geneviève; Bouchard, Véronique; Han, Jiahuai; Landry, Jacques; Beaulieu, Jean‐François; Vézina, Anne; Dydensborg, Anders Bondo; Gauthier, Rémy; Côté, André; Drolet, Jean-Francois; Lareau, Francois

doi:10.1053/gast.2002.37072

Cited by 61 publications

(120 citation statements)

References 54 publications

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“…Jijon et al (2004) reported that NIK-dependent p65-mediated gene expression was dependent on p38 MAPK phosphorylation of p65. We also show that overexpression of NIK in the IEC-18 cells resulted in greater nuclear p65 in detached cells, and while p38 is activated by detachment (Vachon et al, 2001;Rosen et al, 2002, and results not shown), NF-kB activation was not prevented by the p38 inhibitor SB203580. Furthermore, the increase did not result in a significantly greater number of cells surviving to 24 h post detachment.…”

Section: Discussionsupporting

confidence: 50%

Activation of NF-κB following detachment delays apoptosis in intestinal epithelial cells

et al. 2005

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Section: Discussionsupporting

confidence: 50%

Activation of NF-κB following detachment delays apoptosis in intestinal epithelial cells

et al. 2005

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“…It was previously reported that Caco2 cells exhibit distinct profiles of p38 isoform expression depending on the differentiation status. Undifferentiated cells produce p38a, b and g, whereas differentiated cells synthesize p38a, g and d. 25 Conversely, the expression profile of p38 isoforms in HT29 cells remained unchanged regardless of the differentiation status. In fact, the cells expressed p38a, g and d despite NaB treatment (Figure 5a and b).…”

Section: Resultsmentioning

confidence: 95%

A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

et al. 2006

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Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38a/b kinases. We report that p38a is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38a activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38a as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38a pathway in the treatment of colorectal cancer. Colorectal cancer is a major health concern, with more than 1 000 000 new cases and 500 000 deaths expected worldwide per year.1 Prognostic evaluation is currently based on histological appearance, and there are no molecular markers internationally recognized as standard predictor factors. The conventional therapy involving surgery and adjuvant therapy seems to give rise to improvements in progression-free and overall survival. Nevertheless about 50% of patients die within 5 years owing to metastasis or recurrent disease.2 The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of cell cycle and cell death regulatory pathways in tumor cells in order to identify differential cellular effects of agents that may have a direct impact on cancer therapy.During the last decade, a number of deacetylase inhibitors (DI) have been identified. These DI induce tumor cells to undergo growth arrest, differentiation, and/or apoptosis in culture and in animal models, at doses that seem to be nontoxic and appear to be selective. Butyrate, a DI that is naturally formed in the human colon, is able to reduce the size and the number of tumors in rat models of bowel cancer.3 In vitro, sodium butyrate (NaB) is a potent differentiating agent for several colorectal cancer cell lines (CRCs).4-6 NaB-mediated cell cycle withdrawal of CRCs appears to be dependent on acetylation of histones and consequent changes in transcription, requiring continuous protein synthesis and the expression of p21. 7 It has recently been shown that 1 mM NaB is the best working concentration to activate the differentiation program in CRCs without triggering apoptosis, whereas 5 mM NaB is sufficient to induce a p53-independent...

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“…(iii) Nontransformed gastrointestinal cell lines are crypt-like (IEC-6) rather than terminally differentiated epithelial cell lines. There are several reports that have clearly established that intestinal epithelial cell survival and death are subjected to the differentiation state-specific control mechanisms, and undifferentiated crypt cells exhibit a distinct susceptibility to apoptosis/anoikis from differentiated villus cells (39,40). Villin Delays Apoptosis by Inhibiting Caspase-9 and Caspase-3-To characterize the anti-apoptotic function of villin, we analyzed the cleavage of PARP, a substrate of activated caspases in MDCK cells with or without villin expression following camptothecin treatment.…”

Section: Villin-null Mice Demonstrate Increased Epithelial Cell Apoptmentioning

confidence: 99%

A Novel Role for Villin in Intestinal Epithelial Cell Survival and Homeostasis

Wang

Srinivasan

Siddiqui

et al. 2008

Journal of Biological Chemistry

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Apoptosis is a key regulator for the normal turnover of the intestinal mucosa, and abnormalities associated with this function have been linked to inflammatory bowel disease and colorectal cancer. Despite this, little is known about the mechanism(s) mediating intestinal epithelial cell apoptosis. Villin is an actin regulatory protein that is expressed in every cell of the intestinal epithelium as well as in exocrine glands associated with the gastrointestinal tract. In this study we demonstrate for the first time that villin is an epithelial cell-specific anti-apoptotic protein. Absence of villin predisposes mice to dextran sodium sulfate-induced colitis by promoting apoptosis. To better understand the cellular and molecular mechanisms of the anti-apoptotic function of villin, we overexpressed villin in the Madin-Darby canine kidney Tet-Off epithelial cell line to demonstrate that expression of villin protects cells from apoptosis by maintaining mitochondrial integrity thus inhibiting the activation of caspase-9 and caspase-3. Furthermore, we report that the anti-apoptotic response of villin depends on activation of the pro-survival proteins, phosphatidylinositol 3-kinase and phosphorylated Akt. The results of our studies shed new light on the previously unrecognized function of villin in the regulation of apoptosis in the gastrointestinal epithelium.

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Differentiation state-selective roles of p38 isoforms in human intestinal epithelial cell anoikis

Cited by 61 publications

References 54 publications

Activation of NF-κB following detachment delays apoptosis in intestinal epithelial cells

Activation of NF-κB following detachment delays apoptosis in intestinal epithelial cells

A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

A Novel Role for Villin in Intestinal Epithelial Cell Survival and Homeostasis

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