Central role of p53 on regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in mammary carcinoma.
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.
Pal
S
S
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Datta
K
K
Mukhopadhyay
D
D
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019061:src-Family Kinases / Q000378:metabolism
D016228:Endothelial Growth Factors; D008222:Lymphokines; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019061:src-Family Kinases