RGD Reference Report - Induction of p53 by GKLF is essential for inhibition of proliferation of vascular smooth muscle cells. - Rat Genome Database

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Induction of p53 by GKLF is essential for inhibition of proliferation of vascular smooth muscle cells.

Authors: Wassmann, S  Wassmann, K  Jung, A  Velten, M  Knuefermann, P  Petoumenos, V  Becher, U  Werner, C  Mueller, C  Nickenig, G 
Citation: Wassmann S, etal., J Mol Cell Cardiol. 2007 Sep;43(3):301-7. Epub 2007 Jun 16.
RGD ID: 1643591
Pubmed: PMID:17659301   (View Abstract at PubMed)
DOI: DOI:10.1016/j.yjmcc.2007.06.001   (Journal Full-text)

Proliferation of vascular smooth muscle cells (VSMC) plays an important role in the pathogenesis of atherosclerosis and restenosis. Recent studies have demonstrated that the transcription factor gut-enriched Kruppel-like factor (GKLF, KLF4) is involved in redox-sensitive growth arrest of VSMC. We investigated the role of GKLF in VSMC proliferation and differentiation and the potentially important interaction with the tumor suppressor gene p53. Cultured rat aortic VSMC were transfected with GKLF sense and antisense constructs by electroporation. GKLF enhanced the mRNA expression of the differentiation marker SM22-alpha, but had no effect on the expression of alpha-smooth muscle actin (real-time RT-PCR, Western blot). Overexpression of GKLF significantly reduced VSMC proliferation (cell count, BrdU FACS analysis). Because p53 is essential for proliferation processes, the effect of GKLF on p53 gene expression was investigated. GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression (luciferase reporter assay, real-time PCR, Western blot). Consistently, GKLF overexpression induced an enhanced expression of the p53 target genes p21(WAF1/Cip1) and Mdm2. Co-transfection experiments revealed that the growth arrest induced by GKLF sense transfection was completely abolished by co-transfection of p53 antisense constructs, whereas the reduced proliferation exerted by p53 sense transfection was not inhibited by GKLF antisense transfection, suggesting that p53 induction is essential for the interference of GKLF with VSMC proliferation. Finally, stimulation of VSMC with hydroxyl radicals increased expression of GKLF and p53 and reduced cell proliferation. The transcription factor GKLF induces inhibition of proliferation of VSMC which is mechanistically linked to a GKLF-induced enhancement of the expression of the tumor suppressor gene p53.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
DNA-binding transcription activator activity, RNA polymerase II-specific  IDA 1643591 RGD 
sequence-specific DNA binding  IDA 1643591 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Klf4  (KLF transcription factor 4)
Tp53  (tumor protein p53)

Objects referenced in this article
Gene Mdm2 MDM2 proto-oncogene Rattus norvegicus

Additional Information