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Expression of the vascular endothelial growth factor gene is inhibited by p73
B Salimath1, D Marmé, G Finkenzeller
1Department of Biochemistry, Manasagangothi Campus, University of Mysore, Mysore 570006, Karnataka, India.
Abstract:
Recently, p73, a new member of the p53 family, has been cloned and mapped to chromosome 1p36, a region that is frequently deleted in a variety of human cancers. p73 can activate p53-responsive promoters and induce apoptosis when overexpressed in certain p53-deficient tumor cells. In contrast to p53, analysis of the p73 gene in several human solid tumors did not reveal loss of p73 expression or mutations in the p73 gene. However, transcriptional silencing of the p73 gene by hypermethylation of a CpG island was observed in several leukemias and lymphomas. These lymphoid neoplasms also show increased expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of angiogenesis. To evaluate a possible relationship between p73 status and VEGF expression, we have studied the effect of ectopically expressed p73 on the regulation of the VEGF gene. Our results demonstrate that p73 can down-regulate endogenous VEGF gene expression on mRNA and protein level. This effect is mediated by transcriptional repression of the VEGF promoter and involves the promoter region -85 to -50 bp, containing a cluster of Sp 1 binding sites. Our results suggest a regulatory role for p73 in tumor angiogenesis. Oncogene (2000) 19, 3470 - 3476
Insights
The p73 protein, a p53 family member, down-regulates vascular endothelial growth factor (VEGF) gene expression. This finding suggests p73 plays a role in controlling tumor angiogenesis.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The p73 gene, a p53 family member, is located on chromosome 1p36, a region frequently deleted in human cancers.
- p73 can activate p53-responsive promoters and induce apoptosis in p53-deficient tumor cells.
- Unlike p53, p73 expression and gene mutations are not commonly found in solid tumors, but transcriptional silencing via hypermethylation occurs in leukemias and lymphomas.
Purpose of the Study:
- To investigate the relationship between p73 status and vascular endothelial growth factor (VEGF) expression in lymphoid neoplasms.
- To determine the effect of ectopically expressed p73 on the regulation of the VEGF gene.
Main Methods:
- Studied the effect of ectopically expressed p73 on endogenous VEGF gene expression.
- Analyzed VEGF mRNA and protein levels.
- Investigated the transcriptional regulation of the VEGF promoter, focusing on the region -85 to -50 bp.
Main Results:
- Ectopically expressed p73 significantly down-regulates endogenous VEGF gene expression at both mRNA and protein levels.
- p73 mediates this effect through transcriptional repression of the VEGF promoter.
- The repression involves the promoter region containing Sp1 binding sites (-85 to -50 bp).
Conclusions:
- p73 acts as a negative regulator of VEGF gene expression.
- p73 may play a crucial role in regulating tumor angiogenesis.
- Transcriptional silencing of p73 by hypermethylation in certain cancers could contribute to increased VEGF expression and angiogenesis.