The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts.
Integrin-mediated cell adhesion to extracellular matrix proteins is known to promote cell survival, whereas detachment from the matrix can cause rapid apoptotic death in some cell types. Contrary to this paradigm, we show that fibroblast adhesion to the angiogenic matrix protein CCN1 (CYR61) induces apoptosis, whereas endothelial cell adhesion to CCN1 promotes cell survival. CCN1 induces fibroblast apoptosis through its adhesion receptors, integrin alpha6beta1 and the heparan sulfate proteoglycan (HSPG) syndecan-4, triggering the transcription-independent p53 activation of Bax to render cytochrome c release and activation of caspase-9 and -3. Neither caspase-8 activity nor de novo transcription or translation is required for this process. These results show that cellular interaction with a specific matrix protein can either induce or suppress apoptosis in a cell type-specific manner and that integrin alpha6beta1-HSPGs can function as receptors to induce p53-dependent apoptosis.
Todorovic
Viktor
V
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607, USA.
Chen
Chih-Chiun
CC
Hay
Nissim
N
Lau
Lester F
LF
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61; D042783:Endothelial Cells / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology*; D039121:Integrin alpha6beta1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D014176:Protein Biosynthesis; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D053671:Syndecan-4; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D039121:Integrin alpha6beta1; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508304:SDC4 protein, human; C508307:Sdc4 protein, rat; D053671:Syndecan-4; D016159:Tumor Suppressor Protein p53; D020169:Caspases