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Cysteine-rich protein 61 (Cyr61/CCN1) is an angiogenic factor and a member of a family of growth factor-inducible immediate-early genes with functions in cell adhesion, pro-liferation and differentiation.We investigated the regulatory mechanisms and signaling pathways involved inCyr61/ CCN1gene activation in smoothmuscle cells.Treatment of these cells with sphingosine 1-phosphate (S1P), a bioactive lysolipid, increased rapidly but transiently the expression of theCyr61/CCN1gene at both themRNAandprotein levels | Eur. J. Biochem. 270 3408-3421 2003 FEBS 2003 doi 10.1046 j.1432-1033.2003.03723.x Regulation of Cyr61 CCN1 gene expression through RhoA GTPase and p38MAPK signaling pathways Role of CREB and AP-1 transcription factors Ji-Soo Han1 Edward Macarak1 Joel Rosenbloom1 Kwang Chul Chung2 and Brahim Chaqour1 1 University of Pennsylvania Department of Anatomy and Cell Biology Philadelphia PA USA 2Department of Biology College of Sciences Yonsei University Seoul Korea Cysteine-rich protein 61 Cyr61 CCN1 is an angiogenic factor and a member of a family of growth factor-inducible immediate-early genes with functions in cell adhesion proliferation and differentiation. We i n vesii ga ted th e ix g Ll aitrny mechanisms and signaling pathways involved in Cyr61 CCN1 gene activation in smooth muscle cells. Treatment of these cells with sphingosine 1-phosphate S1P a bioactive lysolipid increased rapidly but transiently the expression of the Cyr61 CCN1 gene at both the mRNA and protein levels. Cyr61 CCN1 mRNA stability was not altered but the transcription rate of the Cyr61 CCN1 gene was increased fivefold in isolated nuclei from S1P-stimulated cells indicating that the level of control is primarily transcriptional. Transfection experiments showed that a 936-bp promoter fragment of the human Cyr61 CCN1 gene is functional and induces a reporter gene activity in S1P-treated cells. Using a combination of cis-element mutagenesis and expression of dominant negative inhibitors of transcription factors we showed that both a CRE and AP-1 site and their cognate transcription factors cAMP response element binding protein CREB and AP-1 were responsible for the promoter activity in S1P-stimulated cells. Furthermore by using either pharmacological inhibitors or active forms of known signaling molecules we showed that inducible Cyr61 CCN1 gene expression occurs through RhoA GTPase and that additional signaling through the p38 pathway is required. In particular p38 seems to regulate Cyr61 CCN1 .
