Document Detail

Central role of p53 on regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in mammary carcinoma.
MedLine Citation:
PMID:  11559575     Owner:  NLM     Status:  MEDLINE    
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 Sp1 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.
S Pal; K Datta; D Mukhopadhyay
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  61     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2001 Sep 
Date Detail:
Created Date:  2001-09-17     Completed Date:  2001-10-11     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6952-7     Citation Subset:  IM    
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
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MeSH Terms
Breast Neoplasms / enzymology,  genetics,  metabolism*
Cell Hypoxia / physiology
Down-Regulation / physiology
Endothelial Growth Factors / biosynthesis*,  genetics
Enzyme Activation
Gene Expression Regulation, Neoplastic / physiology*
Genes, p53 / physiology*
Lymphokines / biosynthesis*,  genetics
Promoter Regions, Genetic
RNA, Messenger / biosynthesis,  genetics
Sp1 Transcription Factor / antagonists & inhibitors,  metabolism,  physiology
Transcriptional Activation / physiology
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / metabolism,  physiology*
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
src-Family Kinases / metabolism
Grant Support
Reg. No./Substance:
0/Endothelial Growth Factors; 0/Lymphokines; 0/RNA, Messenger; 0/Sp1 Transcription Factor; 0/Tumor Suppressor Protein p53; 0/Vascular Endothelial Growth Factor A; 0/Vascular Endothelial Growth Factors; EC Kinases

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