Central role of p53 on regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in mammary carcinoma

S. Pal, Kaustubh Datta, D. Mukhopadhyay

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Abstract

The process of angiogenic switching is one of the most important factors in the growth and development of breast tumors. Vascular permeability factor/ vascular endothelial growth factor (VPF/VEGF) is considered to be the most important directly acting angiogenic protein that has been shown to be up-regulated in breast cancer cells. Hypoxia seems to be an important stimulus for inducing VPF/VEGF mRNA expression in human mammary tumors. Here, we have studied the roles of the tumor suppressor gene p53 and the proto-oncogene c-Src in regulating the transcription of VPF/VEGF in breast cancer cell lines MCF-7 and MDA-MB 435 under both normoxic and hypoxic conditions, p53 significantly inhibited the transcription of VPF/VEGF involving the transcription factor Sp1. Increased binding of Spl to the VPF/VEGF promoter has been observed when the cells were exposed to hypoxia. It has been shown that p53 makes a complex with Sp1 and inhibits its binding to the VPF/VEGF promoter to prevent the transcriptional activation. Furthermore, c-Src kinase activity was found to be increased in the hypoxic condition, and in the presence of antisense of Src, there was down-regulation of the total mRNA level and also the promoter activity of VPF/VEGF. The present study indicates that p53 can also inhibit the hypoxic induction of Src kinase activity and thereby may prevent VPF/VEGF transcription. Taken together, our data suggest a central role of p53, through which it can inhibit VPF/VEGF expression by regulating the transcriptional activity of Sp1 and also by down-regulating the Src kinase activity, under both normoxic and hypoxic conditions.

Original languageEnglish (US)
Pages (from-to)6952-6957
Number of pages6
JournalCancer Research
Volume61
Issue number18
StatePublished - Sep 15 2001

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Vascular Endothelial Growth Factor A
Breast Neoplasms
src-Family Kinases
Angiogenic Proteins
src Genes
Sp1 Transcription Factor
Messenger RNA
Tumor Suppressor Genes
Growth and Development
Transcriptional Activation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Central role of p53 on regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in mammary carcinoma. / Pal, S.; Datta, Kaustubh; Mukhopadhyay, D.

In: Cancer Research, Vol. 61, No. 18, 15.09.2001, p. 6952-6957.

Research output: Contribution to journalArticle

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