Transcriptional regulation of the c-H-ras1 gene by the P53 protein is implicated in the development of human endometrial and ovarian tumours.

Abstract

The human c-H-ras1 gene contains within the first intron a p53 element, which functions as a transcriptional enhancer. Using nuclear extracts from human endometrial and ovarian tumours in gel retardation assays, we examined the binding levels of the P53 protein to the H-ras element in tumour versus the adjacent normal tissue. Elevated P53 binding in the tumour tissue was found in 5/12 (42%) endometrial and in 2/5 (40%) ovarian specimens and these cases were found to overexpress wild-type P53. Loss of P53 binding to the H-ras element due to p53 mutations, was observed in 3/12 (25%) endometrial and in 1/5 (20%) ovarian cases. Similar P53 binding levels to the H-ras element were found in 4/12 (33%) endometrial and in 2/5 (40%) ovarian pairs showing normal expression of wild-type P53. Overexpression of the Ras p21 protein correlated with elevated binding and increased nuclear levels of wild-type P53. Our results suggest that P53 protein alterations, participate in the development of human gynecological neoplasias through aberrant transcriptional regulation of the H-ras proto-oncogene.