Phosphatidylinositol 3-Kinase Controls Human Intestinal Epithelial Cell Differentiation by Promoting Adherens Junction Assembly and p38 MAPK Activation

Laprise, Patrick; Chailler, Pierre; Houde, Mathieu; Beaulieu, Jean‐François; Boucher, Marie-Josée; Rivard, Nathalie

doi:10.1074/jbc.m110235200

Cited by 157 publications

(203 citation statements)

References 48 publications

(61 reference statements)

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“…Several different signaling pathways are required and act in a combinatorial manner to maintain homeostasis in the normal intestinal epithelium. Some of the pathways identified to date include the Wnt pathway (2), the Notch pathway (3), the Hedgehog system (4), members of the transforming growth factor-␤ family including the bone morphogenetic proteins (5), and the phosphatidylinositol 3-kinase pathway (6). The intestine specific gene expression requires the tightly regulated activity of transcription factors, including the well characterized key factors HNF1␣/␤, 2 HNF4␣, GATA factors, ETS, CDX1, and CDX2 (7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Genome-wide Analysis of CDX2 Binding in Intestinal Epithelial Cells (Caco-2)

Boyd

Hansen

Jensen

et al. 2010

Journal of Biological Chemistry

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confidence: 99%

Genome-wide Analysis of CDX2 Binding in Intestinal Epithelial Cells (Caco-2)

Boyd

Hansen

Jensen

et al. 2010

Journal of Biological Chemistry

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confidence: 99%

“…During enterocyte differentiation of CRCs the ERK pathway is switched off, whereas PI 3 K class I and p38 activities are increased and essential for full differentiation. 5,9 It has been suggested that p38a could activate the intestinal-specific homeobox transcription factor CDX2 probably by phosphorylation. 10 This mechanism resembles that described for p38a/b in muscle cells, where they phosphorylate the transcription factor MEF2 and the SWI/SNF subunit BAF60 to remodel chromatin and activate tissue-specific transcription.…”

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confidence: 99%

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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“…12). E-cadherin-mediated cell-cell contacts also promote intestinal epithelial cell differentiation (21,28) and survival of prostate and breast epithelial cells (13).…”

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confidence: 99%

E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells

Kim¹,

Schein²,

Nadel³

2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Kim, Suil, Aaron J. Schein, and Jay A. Nadel. E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 289: L1049 -L1060, 2005. First published July 29, 2005; doi:10.1152/ajplung.00388.2004In previous work, we showed that epidermal growth factor receptor (EGFR) activation causes mucin expression in airway epithelium in vivo and in human NCI-H292 airway epithelial cells and normal human bronchial epithelial (NHBE) cells in vitro. Here we show that the cell surface adhesion molecule, E-cadherin, promotes EGFR-mediated mucin production in NCI-H292 cells in a cell density-and cell cycle-dependent fashion. The addition of the EGFR ligand, transforming growth factor (TGF)-␣, increased MUC5AC protein expression markedly in dense, but not in sparse, cultures. MUC5AC-positive cells in dense cultures contained 2 N DNA content and did not incorporate bromodeoxyuridine, suggesting that they develop via cell differentiation and that a surface molecule involved in cell-cell contact is important for EGFRmediated mucin production. In support of this hypothesis, in dense cultures of NCI-H292 cells and in NHBE cells at air-liquid interface, blockade of E-cadherin-mediated cell-cell contacts decreased EGFRdependent mucin production. E-cadherin blockade also increased EGFR-dependent cell proliferation and TGF-␣-induced EGFR tyrosine phosphorylation in dense cultures of NCI-H292 cells, suggesting that E-cadherin promotes EGFR-dependent mucin production and inhibits EGFR-dependent cell proliferation via modulation of EGFR phosphotyrosine levels. Furthermore, in dense cultures, E-cadherin blockade decreased the rate of EGFR tyrosine dephosphorylation, implicating an E-cadherin-dependent protein tyrosine phosphatase in EGFR dephosphorylation. Thus E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC production, and our results suggest that this occurs via a pathway involving protein tyrosine phosphatase-dependent EGFR dephosphorylation. epidermal growth factor receptor; airway epithelium THE PRODUCTION OF MUCIN-CONTAINING goblet cells in the airways is an important feature in diseases of mucus hypersecretion such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, nasal polyps, and bronchiectasis (reviewed in Ref. 38). Several years ago, Takeyama et al. (61) showed that epidermal growth factor receptor (EGFR) activation causes mucin production in airway epithelial cells in vivo and in human NCI-H292 airway epithelial cells in vitro. Subsequent studies have implicated EGFR activation in mucin upregulation (44) by many stimuli (7, 24, 26, 31, 32, 50 -52, 60, 62), suggesting that the EGFR cascade is a convergent pathway for mucin production by airway epithelial (goblet) cells.Biological responses to EGFR signaling are pleiotropic and include proliferation, differentiation, and apoptosis (reviewed in Ref. 19). In multicellular organisms, cell neighbors influence cell growth and differentiation. When normal e...

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Phosphatidylinositol 3-Kinase Controls Human Intestinal Epithelial Cell Differentiation by Promoting Adherens Junction Assembly and p38 MAPK Activation

Cited by 157 publications

References 48 publications

Genome-wide Analysis of CDX2 Binding in Intestinal Epithelial Cells (Caco-2)

Genome-wide Analysis of CDX2 Binding in Intestinal Epithelial Cells (Caco-2)

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

E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells

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