Rins, even in adherent cells, can also induce apoptosis by the direct recruitment and activation of caspase-8 (Stupack et al., 2001). Moreover, unligated integrin five 1 can trigger the release with the mitochondrial protein Bit1 into the cytoplasm, thereby activating a caspase-independent mechanism of cell death (Jan et al., 2004). As a result, integrin-mediated cell adhesion events play vital roles inside the manage of apoptosis. CCN1 (CYR61) can be a secreted matrix-associated heparinbinding protein that includes structural domains common to ECM proteins, like the von Willebrand aspect kind C repeat, the thrombospondin kind 1 repeat, and also the COOH terminus of muscins (Lau and Lam, 1999). Encoded by a growth factor nducible immediate early gene, CCN1 regulates a broad spectrum of cellular activities, including cell adhesion,The Rockefeller University Press eight.00 The Journal of Cell Biology, Vol. 171, No. 3, November 7, 2005 55968 http://www.jcb.org/cgi/doi/10.1083/jcb.JCBmigration, proliferation, survival, and differentiation. Mechanistically, CCN1 acts by way of direct binding to a minimum of five distinct integrins, which mediate CCN1 functions inside a cell typeand context-dependent manner (Lau and Lam, 2005). For instance, CCN1 promotes proangiogenic activities in activated endothelial cells by means of integrin v 3 (Leu et al., 2002) and supports fibroblast and smooth muscle cell adhesion by way of integrin six 1 with heparan sulfate proteoglycans (HSPGs) as coreceptors (Chen et al., 2000; Grzeszkiewicz et al., 2002). Adhesion of major human fibroblasts to immobilized CCN1 induces adhesive signaling, such as the formation of filopodia and lamellipodia and activation of FAK, paxillin, Rac, and Erk1/2, culminating within the regulation of genes that manage angiogenesis, inflammation, and matrix remodeling (Chen et al., 2001a,b). Consistent with these activities, Ccn1 expression in adulthood is connected with 5-HT2 Receptor Antagonist Source biological and pathological contexts in which angiogenesis and inflammation play significant roles, including wound healing, restenosis, atherosclerosis, and tumorigenesis (Grzeszkiewicz et al., 2002; for assessment see Menendez et al., 2003). Furthermore, CCN1 induces angiogenesis each in vitro and in vivo and is essential for thriving vascular development, as evidenced by the embryonic lethality of Ccn1-null mice resulting from placental vascular insufficiency and loss of embryonic vessel integrity (Babic et al., 1998; Mo et al., 2002). CCN1 protects activated endothelial cells from apoptosis by ligation to integrin v 3 and promotes survival in MCF7 breast cancer cells by up-regulation of PLK4 Purity & Documentation X-linked inhibitor of apoptosis (Leu et al., 2002; Lin et al., 2004). However, Ccn1 expression has been related with cell death in the hippocampal progenitor cell line H19 and in endometrial cancer cells (Kim et al., 2003; Chien et al., 2004), suggesting that CCN1 might regulate cell survival differently in distinct cell sorts. We show that CCN1 can promote the survival of activated endothelial cells but induces apoptosis in fibroblasts. Paradoxically, CCN1 induces fibroblast apoptosis as an adhesion substrate via its adhesion receptors, integrin 6 1 along with the HSPG syndecan-4, regardless of activation of the prosurvival protein FAK. Ligation of CCN1 towards the adhesion receptors in fibroblasts, neither of which has previously been implicated in apoptosis, benefits in the transcription-independent p53 activation of Bax and cytochrome c release, triggering the activation of caspase-.
