The p53 Tumor Suppressor Protein Does Not Regulate Expression of Its Own Inhibitor, MDM2, Except under Conditions of Stress

ABSTRACT MDM2 is an important regulator of the p53 tumor suppressor protein. MDM2 inhibits p53 by binding to it, physically blocking its ability to transactivate gene expression, and stimulating its degradation. In cultured cells, mdm2 expression can be regulated by p53. Hence, mdm2 and p53 can interact to form an autoregulatory loop in which p53 activates expression of its own inhibitor. The p53/MDM2 autoregulatory loop has been elucidated within cultured cells; however, regulation of mdm2 expression by p53 has not been demonstrated within intact tissues. Here, we examine the role of p53 in regulating mdm2 expression in vivo in order to test the hypothesis that the p53/MDM2 autoregulatory loop is the mechanism by which low levels of p53 are maintained. We demonstrate that basal expression of mdm2 in murine tissues is p53 independent, even in tissues that express functional p53. Transcription ofmdm2 is induced in a p53-dependent manner following gamma irradiation, indicating that p53 regulates mdm2 expression in vivo following a stimulus. The requirement for a stimulus to activate p53-dependent regulation of mdm2 expression in vivo appeared to differ from the situation in early-passage mouse embryo fibroblasts, where mdm2 expression is enhanced by the presence of p53. Analysis of mdm2 expression in intact and dispersed embryos revealed that establishment of mouse embryo fibroblasts in culture induces p53-dependent mdm2expression, suggesting that an unknown stimulus activates p53 function in cultured cells. Together, these results indicate that p53 does not regulate expression of its own inhibitor, except in response to stimuli.