Progesterone up-regulates p27 through an increased binding of the progesterone receptor-A-p53 protein complex onto the non-canonical p53 binding motif in HUVEC

The Journal of Steroid Biochemistry and Molecular Biology
Sung-Po HsuWen-Sen Lee

Abstract

We previously demonstrated that progesterone (P4) up-regulated p53 expression, which in turn increased p21 and p27 expression, and finally resulted in proliferation inhibition in human umbilical vein endothelial cells (HUVEC). While a direct transcriptional activation of p21 by p53 protein has been clearly elucidated, the mechanism by which p53 induces p27 expression has not been documented. In this study, we identified three putative p53 protein binding domains at the p27 promoter. Luciferase assay showed that the activity of ectopically introduced p27 promoter constructs containing the potential p53 protein binding region was significantly increased by P4. Immunoblotting analysis indicated that P4 increased the level of p53 protein. Treatment with pifithrin-α-HBr (PFTα), a specific blocker of p53-responsive gene transactivation, reduced the P4-increased p27 promoter activity and p27 protein expression. Transfection with dominant-negative mutants of p53 (C135Y, R175H and R248 W) abolished the P4-increased p27 promoter activity. Moreover, deletion or TCCT nucleotide sequence fill-in at the core site of any of p53 protein binding domains led to the irresponsiveness of the p27 promoter to P4 treatment. Interestingly, immunoprecip...Continue Reading

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