Sci. STKE, 15 November 2005
APOPTOSIS Life or Death Signal
Cells receive signals from the extracellular matrix (ECM), and many cells require attachment for ECM-dependent cell survival. However, Todorovic et al. report that the matrix protein CCN1 transmits a prosurvival signal to endothelial cells but an apoptosis-inducing signal to fibroblasts. Experiments were performed with human umbilical vein endothelial cells (HUVECs), primary human skin fibroblasts (HSFs), and the Rat1a fibroblast cell line. All cells tested adhered to CCN1, yet CCN1 protected only the HUVECs from apoptosis triggered by serum withdrawal. The presence of soluble or immobilized CCN1 actually increased the number of apoptotic Rat1a and HSF cells, with Rat1a cells being the most sensitive. CCN1 promoted Rat1a cell apoptosis even in the presence of growth factors and despite engaging integrins and stimulating focal adhesion kinase phosphorylation, paxillin phosphorylation, and transient phosphorylation of c-Jun N-terminal kinase. Using various selective inhibitors and antibodies, the authors showed that CCN1 mediated its apoptotic signal through interactions with the heparin sulfate proteoglycan syndecan-4 and the integrin α6β1, both in Rat1a cells and HSFs. CCN1-mediated apoptosis did not require de novo protein synthesis; instead, p53 appeared to mediate Bax activation. Expression of the genetic suppressor element GSE56 or treatment of cells with cyclic pifithrin, both of which inhibit p53, prevented CCN1-stimulated apoptosis. Mouse fibroblasts deficient in p53 were also resistant to CCN1-induced apoptosis, but expression of p53 in those restored CCN1 sensitivity. Thus, CCN1 appears to deliver a dual signal, one that allows cell spreading and attachment through focal adhesions and also one that engages the cell death machinery through p53 stimulation of the proapoptotic molecule Bax.
Citation: Life or Death Signal. Sci. STKE 2005, tw404 (2005).
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