Activation of the p21 Pathway of Growth Arrest and Apoptosis by the β4 Integrin Cytoplasmic Domain

Clarke, Allison; Lotz, Margaret M.; Chao, Celia; Mercurio, Arthur M.

doi:10.1074/jbc.270.39.22673

Cited by 121 publications

(75 citation statements)

References 25 publications

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“…Ligation of integrin a5b1 in a5-transfected tumor cells which exhibit reduced proliferation as compared with untransfected cells, also prevented apoptosis by inducing Bcl-2 expression (Stromblad et al, 1996). Ligation of integrin avb3 in endothelial cells suppresses p53 activity and increases the Bcl-2:Bax ratio, promoting cell survival (Clarke et al, 1995;Stromblad et al, 1996). In contrast, blocking integrin avb3 ligation with integrin antagonists induced p53 activation and blocked Bcl-2 expression (Stromblad et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Rho-dependent cell spreading activated by E.coli cytotoxic necrotizing factor 1 hinders apoptosis in epithelial cells

et al. 1998

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Cell-cell and cell-matrix interactions play a pivotal role in numerous cell functions including cell survival and death. In this work, we report evidence that the Rho-dependent cell spreading activated by a protein toxin from E. coli, the cytotoxic necrotizing factor 1 (CNF1), is capable of hindering apoptosis in HEp-2 cells. In addition to the promotion of cell spreading, CNF1 protects cells from the experimentallyinduced rounding up and detachment and improves the ability of cells to adhere to each other and to the extracellular matrix by modulating the expression of proteins related to cell adhesion. In particular, the expression of integrins such as a 5 , a 6 and a v , as well as of some heterotypic and homotypic adhesion-related proteins such as the Focal Adhesion Kinase, E-cadherin, a and b catenins were significantly increased in cells exposed to CNF1. Our results suggest, however, that the promotion of Rho-dependent cell spreading is the key mechanism in protecting cells against apoptosis rather than cell adhesion per se. A toxin inducing cell spreading without activating Rho, such as Cytochalasin B, was in fact ineffective in favouring cell survival. These data are of relevance (i) for the understanding of the role of the actin-dependent and especially Rho-dependent cellular activities involved in apoptosis regulation and (ii) in providing some clues to understanding the mechanisms by which bacteria, by controlling cell fate, might exert their pathogenic activity.

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Section: Discussionmentioning

confidence: 99%

Rho-dependent cell spreading activated by E.coli cytotoxic necrotizing factor 1 hinders apoptosis in epithelial cells

et al. 1998

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“…For example, while previous reports have shown that ligation of α5β1 or α6β4 integrins by fibronectin or laminin respectively will activate ERK and stimulate cell proliferation [38,56,57], expression of the α5β1 receptor in transformed CHO cells promotes adhesion to fibronectin, but induces growth [70]. Similarly, introduction of the α6β4 integrin into the colon carcinoma cell line RKO permits adhesion to laminin, leading to growth inhibition and the induction of the cyclin kinase inhibitor p21 [71]. A comparative analysis of MAPK activity following ligation of a particular integrin by a given ligand in cells with opposite biological responses might help to clarify two unresolved questions.…”

Section: Integrin-dependent Growth Inhibitionmentioning

confidence: 99%

Extracellular matrix and integrin signalling: the shape of things to come

Boudreau

Jones

1999

Biochemical Journal

411

139

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The extracellular matrix (ECM) and integrins collaborate to regulate gene expression associated with cell growth, differentiation and survival. Biochemical and molecular analyses of integrin signalling pathways have uncovered several critical cytoplasmic proteins that link the ECM and integrins to intracellular pathways that may contribute to anchorage-dependent growth. A large body of evidence now indicates that the non-receptor protein kinases focal adhesion kinase (FAK) and specific members of the mitogen-activated protein kinases (MAPKs), including the extracellular-signal-regulated kinases (ERKs), mediate these ECM- and integrin-derived signalling events. However, little is known about how FAK and MAPKs contribute to biological processes other than cell proliferation or migration. In addition, remarkably little is known concerning the signalling events that occur in cells that adhere to complex multivalent extracellular matrices via multiple integrin receptors. Given the stringent requirement for attaining a proper morphology in ECM/integrin-directed cell behaviour, it is still not clear how cell shape and tissue architecture impact upon intracellular signalling programmes involving FAK and MAPKs. However, the recent discovery that members of the Rho family of small GTPases are able to regulate ECM/integrin pathways that modulate both cell shape and intracellular signalling provides new insights into how cell morphology and signal transduction become integrated, especially within three-dimensional differentiated tissues.

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“…Epithelial cells depend for their survival upon continuous signaling from ligated growth factor receptors and integrins bound to extracellular matrix proteins (2)(3)(4)(5)(6). Loss of such signaling triggers a default pathway of cell death called anoikis, detachment-induced apoptosis (7).…”

mentioning

confidence: 99%

Re-expression of Detachment-inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells

Beckley

Pauli

Elble

2004

Journal of Biological Chemistry

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The calcium-activated chloride channel hCLCA2 has been identified as a candidate tumor suppressor in human breast cancer. It is greatly down-regulated in breast cancer, and its re-expression suppresses tumorigenesis by an unknown mechanism. To establish a mouse model, we identified the mouse ortholog of hCLCA2, termed mCLCA5, and investigated its behavior in mammary epithelial cell lines and tissues. Expression in the immortalized cell line HC11 correlated with slow or arrested growth. Although rapidly dividing, sparsely plated cells had low levels of expression, mCLCA5 was induced by 10-fold when cells became confluent and 30-fold when cells were deprived of growth factors or anchorage. The apoptosis effector Bax was induced in parallel. Like hCLCA2, mCLCA5 was down-regulated in metastatic mammary tumor cell lines such as 4T1 and CSML-100. Ectopic re-expression in 4T1 cells caused a 20-fold reduction in colony survival relative to vector control. High mCLCA5 expression in stable clones inhibited proliferation and enhanced sensitivity to detachment. Moreover, mCLCA5 was induced in lactating and involuting mammary gland, correlating with differentiation and onset of apoptosis. Together, these results establish mCLCA5 as the mouse ortholog of hCLCA2, demonstrate that mCLCA5 is a detachment-sensitive growth inhibitor, and suggest a mechanism whereby these channels may antagonize mammary tumor progression.

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Activation of the p21 Pathway of Growth Arrest and Apoptosis by the β4 Integrin Cytoplasmic Domain

Cited by 121 publications

References 25 publications

Rho-dependent cell spreading activated by E.coli cytotoxic necrotizing factor 1 hinders apoptosis in epithelial cells

Rho-dependent cell spreading activated by E.coli cytotoxic necrotizing factor 1 hinders apoptosis in epithelial cells

Extracellular matrix and integrin signalling: the shape of things to come

Re-expression of Detachment-inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells

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