Transcriptional activation of the ras oncogenes and implications of BRCA1 in the cell cycle regulation through p53 checkpoint

Aberrant expression of ras genes has been recognized in several human cancers and is associated with the development of the disease. Thus, revealing the mechanisms that regulate the expression of ras genes is critical for understanding their role in the process of tumorigenesis. Transcriptional regulation of the H-ras gene, involves nuclear factors recognizing elements in the promoter region of the gene and hormones; so far, a glucocorticoid response element and a p53 element have been identified. Alternative splicing and specific methylation patterns may regulate the expression of ras genes as well. Altered expression of ras genes has been detected in a variety of human tumours. Differential expression of the ras family genes in breast cancer has shown overexpression of al l three members of ras genes. A significant correlation of overexpression of ras genes and stage of the disease was also observed suggest ing that aberrant expression of the ras genes may be an initial event in breast cancer oncogenesis. Overexpression of Ras p21 protein has been detected in human endometrial and ovarian tumours, due to elevated p53 protein binding on the p53 element of the c-H-ras gene, suggesting that p53 protein participates in the development of human gynecological neoplasias through aberrant transcriptional regulation of the H-ras proto-oncogene. Invest igat ion of the BRCA1 express ion leve ls in re levance wi th the expression levels of p53 , mdm-2 and p21WAF1/CIP1 genes, implicated in cell cycle progression, revealed combined alterations of these genes in sporadic breast cancer specimens, indicating that loss of function of BRCA1 may arrest the cell cycle through p53 checkpoint.