Abstract
Enhanced proliferation of vascular smooth muscle cells (VSMCs) is one of the key features of the pathogenesis of atherosclerosis. The helix-loop-helix protein Inhibitor of DNA binding 3 (Id3) contributes to regulation of VSMC proliferation in a redox-sensitive manner. We investigated the role of Id3 and its interaction with other redox-sensitive genes, the transcription factor Gut-enriched Krüppel-like factor (GKLF, KLF4) and the tumor suppressor gene p53 in the regulation of VSMC proliferation. Cultured rat aortic VSMCs were transfected with Id3 sense and antisense constructs. Overexpression of Id3 significantly enhanced VSMC proliferation. Id3 antisense transfection inhibited VSMC proliferation induced by the physiological stimuli insulin and platelet-derived growth factor (PDGF). Because p53 is essential for the regulation of proliferation processes, the effect of Id3 on p53 expression was investigated. Id3 overexpression led to decreased p53 protein expression. Co-transfection of p53 sense constructs inhibited the enhanced VSMC mitogenicity induced by Id3 sense transfection. GKLF overexpression, which causes growth arrest in VSMCs, reduced Id3 promoter activity and led to decreased Id3 expression. Id3-induced VSMC proliferation was abolished by GKLF sense co-transfection. Finally, strong Id3 expression was found in the neointima of human coronary artery atherosclerotic plaques but not in healthy coronary arteries. These findings reveal a relevant interaction of GKLF, Id3, and p53 for VSMC proliferation which might constitute a general mechanism of growth control in vascular cells.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Lusis F (2000) Atherosclerosis. Nature 407:233–241
Berk BC (1999) Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. J Am Soc Nephrol 10:62–68
Griendling KK, Ushio-Fukai M, Lassegue B, Alexander RW (1999) Angiotensin II signaling in vascular smooth muscle. Hypertension 29:366–373
Müller C, Baudler S, Welzel H, Böhm M, Nickenig G (2002) Identification of a novel redox-sensitive gene, Id3, which mediates angiotensin II-induced cell growth. Circulation 105:2423–2428
Nickenig G, Baudler S, Müller C, Werner C, Werner N, Welzel H, Strehlow K, Böhm M (2002) Redox-sensitive vascular smooth muscle cell proliferation is mediated by GKLF and Id3 in vitro and in vivo. FASEB J 16:1077–1086
Prabhu S, Ignatova A, Park ST (1997) Regulation of the expression of cyclin dependent kinase inhibitor p21 by E2A and Id proteins. Mol Cell Biol 17:5888–5896
Northon JD, Atherton GT (1998) Coupling of cell growth control and apoptosis functions of Id proteins. Mol Cell Biol 18:2371–2381
Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B (1999) A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J Biol Chem 271:31384–31390
Shie JL, Chen ZY, Fu M, Pestell RG, Tseng CC (2000) Gut-enriched Kruppel-like factor represses cyclin D1 promoter activity through Sp1 motif. Nucleic Acids Res 28:2969–2976
Geiman DE, Ton-That H, Johnson JM, Yang VW (2000) Transactivation and growth suppression by the gut-enriched Kruppel-like factor (Kruppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction. Nucleic Acids Res 28:1106–1113
Shie JL, Chen ZY, O’Brien MJ, Pestell RG, Lee ME, Tseng CC (2000) Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation. Am J Physiol Gastrointest Liver Physiol 279:G806–G814
Yoon HJ, Chen X, Yang VW (2003) Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. J Biol Chem 278:2101–2105
Zhang W, Geiman DE, Shields JM, Dang DT, Mahatan CS, Kaestner KH, Biggs JR, Kraft AS, Yang VW (2000) The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/Cip1 promoter. J Biol Chem 275:18391–18398
Suzuki T, Aizawa K, Matsumura T, Nagai R (2005) Vascular implications of the Krüppel-like family of transcription factors. Arterioscler Thromb Vasc Biol 25:1135–1141
Wassmann S, Wassmann K, Jung A, Velten M, Knuefermann P, Petoumenos V, Becher U, Werner C, Mueller C, Nickenig G (2007) Induction of p53 by GKLF is essential for inhibition of proliferation of vascular smooth muscle cells. J Mol Cell Cardiol 43:301–307
Braun-Dullaeus RC, Mann MJ, Ziegler A (1999) A novel role fort he cyclin-dependent kinase inhibitor p27(Kip1) in angiotensin II-stimulated vascular smooth muscle cell hypertrophy. J Clin Invest 104:815–823
Acknowledgments
The excellent technical assistance provided by Isabel Paez-Maletz, Susanne Schnell, and Bianca Klöckner is greatly appreciated. This study was supported by the Deutsche Forschungsgemeinschaft (DFG). We thank Prof. Dr. Michael Böhm, Homburg, Germany, for kindly providing human coronary artery sections.
Author information
Authors and Affiliations
Corresponding author
Additional information
Kerstin Wassmann and Cornelius Mueller contributed equally to this study.
Rights and permissions
About this article
Cite this article
Wassmann, K., Mueller, C.F.H., Becher, U.M. et al. Interaction of Inhibitor of DNA binding 3 (Id3) with Gut-enriched Krüppel-like factor (GKLF) and p53 regulates proliferation of vascular smooth muscle cells. Mol Cell Biochem 333, 33–39 (2010). https://doi.org/10.1007/s11010-009-0201-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-009-0201-7