Vascular smooth muscle cell-specific regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1) transcription by Sp1 is mediated via distinct cis-acting positive and negative regulatory elements in the proximal p21(WAF1/Cip1) promoter

Journal of Cellular Biochemistry
Mary M Kavurma, Levon M Khachigian

Abstract

Smooth muscle cells (SMC) play a central role in common vascular pathologies such as atherosclerosis and restenosis. Understanding the molecular regulation of SMC proliferation at a transcriptional level may provide important clues for the targeted control of vascular hyperplasia. We recently reported the capacity of the transcription factor Sp1 to down-regulate p21(WAF1/Cip1) production thereby reducing p21(WAF1/Cip1)-cyclin D1-Cdk4 complex formation and inhibiting vascular SMC proliferation (Kavurma and Khachigian [2003] J. Biol. Chem. 278, 32537-32543). We have now localized the Sp1-response elements in the p21(WAF1/Cip1) promoter responsible for p21(WAF1/Cip1) repression in WKY12-22 SMCs. The proximal region of the p21(WAF1/Cip1) promoter contains five distinct Sp1-binding elements that we have termed A, B, C, D, and E. Electrophoretic mobility shift analysis revealed that SMC nuclear Sp1 interacts with all five Sp1-binding sites, and each of these sites is critical for Sp1 repression of the p21(WAF1/Cip1) promoter, since mutation in any one element ablates repression, and in some cases results in activation. In contrast, only elements C, D, and E are bound by Sp1 in endothelial cells. Sp1 overexpression activates the p21(W...Continue Reading

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Citations

Sep 26, 2012·The Journal of Biological Chemistry·Ellen HukkelhovenAndrew Koff
Nov 14, 2014·The FEBS Journal·Kate Beishline, Jane Azizkhan-Clifford
Feb 21, 2009·Plastic and Reconstructive Surgery·Magdalena PlasilovaBabak J Mehrara
Sep 5, 2020·Journal of Cellular and Molecular Medicine·Mengdie ChengHui Xin
May 19, 2005·Cancer Research·Andrei L Gartel, Senthil K Radhakrishnan
Nov 11, 2008·Free Radical Biology & Medicine·Cécile Mazière, Jean-Claude Mazière

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