The mdm2 proto-oncogene.

ABSTRACT

The mouse double minute 2 (mdm2) proto-oncogene was originally discovered as one of three genes that was amplified in a tumorigenic cell line derived from non-transformed Balb/c cells. Consistent with the expression pattern of mdm2 in these cells, it was later shown that the transforming potential of the mdm2 proto-oncogene can be activated by experimental overexpression. Overexpression of mdm2 protein been detected in a number of diverse human malignancies, indicating that this oncogene plays a key role in human carcinogenesis. One mechanism by which mdm2 overexpression may lead to uncontrolled cellular proliferation is through its ability to physically associate with the p53 tumor suppressor and block p53's growth suppressive functions. Forced overexpression of mdm2 has been shown to block the transactivation, cell cycle arrest and apoptotic functions of p53. The mdm2 gene has also been shown to be a transcriptional target of p53 and the induction of p53 transcriptional activity leads to increases in mdm2 RNA and protein levels. Thus, it appears that an auto-regulatory feedback loop exists between these two proteins which keeps the growth suppressive functions of p53 in check during normal cell cycling. However, this block is thought to be overcome during certain cellular insults, including DNA damage, so that p53 can regulate the expression of genes involved in cell cycle arrest and/or apoptosis. Genetic lesions leading to elevated levels of mdm2 likely impair the ability of p53 to orchestrate the expression of genes controlling cell cycle progression during cellular insults. This may lead to the propagation of genetic errors, genomic instability and ultimately to an increase in the rate of tumor cell evolution. There is also recent evidence which suggests that mdm2 may play roles in p53-independent pathways regulating cellular proliferation. mdm2 has recently been shown to interact with the retinoblastoma tumor suppressor protein p(Rb), and the E2F-1 and DP1 transcription factors. These, and other clinical, cellular and biochemical studies relating to the mdm2 oncogene are reviewed here. In addition, a proposed role for mdm2 in pathways controlling cell cycle response to cellular perturbations is presented.