The function of the p53 tumor suppressor protein must be highly regulated because p53 can cause cell death and prevent tumorigenesis. In cultured cells, the p90 MDM2 protein blocks the transcriptional activation domain of p53 and also stimulates the degradation of p53. Here we provide the first conclusive demonstration that p90 MDM2 constitutively regulates p53 activity in homeostatic tissues. Mice with a hypomorphic allele of mdm2 revealed a heretofore unknown role for mdm2 in lymphopoiesis and epithelial cell survival. Phenotypic analyses revealed that both the transcriptional activation and apoptotic functions of p53 were increased in these mice. However, the level of p53 protein was not coordinately increased, suggesting that p90 MDM2 can inhibit the transcriptional activation and apoptotic functions of p53 in a manner independent of degradation. Cremediated deletion of mdm2 caused a greater accumulation of p53, demonstrating that p90 MDM2 constitutively regulates both the activity and the level of p53 in homeostatic tissues. The observation that only a subset of tissues with activated p53 underwent apoptosis indicates that factors other than p90 MDM2 determine the physiological consequences of p53 activation. Furthermore, reduction of mdm2 in vivo resulted in radiosensitivity, highlighting the importance of mdm2 as a potential target for adjuvant cancer therapies.

The p53 tumour-suppressor gene is mutated in 60% of human tumours, and the product of the gene acts as a suppressor of cell division. It is thought that the growth-suppressive effects of p53 are mediated through the transcriptional transactivation activity of the protein. Overexpression of the p53 protein results either in arrest in the G1 phase of the cell cycle or in the induction of apoptosis. Both the level of the protein and its transcriptional transactivation activity increase following treatment of cells with agents that damage DNA, and it is thought that p53 acts to protect cells against the accumulation of mutations and subsequent conversion to a cancerous state. The induction of p53 levels in cells exposed to gamma-irradiation results in cell cycle arrest in some cells (fibroblasts) and apoptosis in others (thymocytes). Cells lacking p53 have lost this cell cycle control and presumably accumulate damage-induced mutations that result in tumorigenesis. Thus, the role of p53 in suppressing tumorigenesis may be to rescue the cell or organism from the mutagenic effects of DNA damage. Loss of p53 function accelerates the process of tumorigenesis and alters the response of cells to agents that damage DNA, indicating that successful strategies for radiation therapy may well need to take into account the tissue of origin and the status of p53 in the tumour.

The p53 inhibitor murine double-minute gene 2 (Mdm2) is a target for potential cancer therapies, however increased p53 function can be lethal. To directly address whether reduced Mdm2 function can inhibit tumorigenesis without causing detrimental side effects, we exploited a hypomorphic murine allele of mdm2 to compare the effects of decreased levels of Mdm2 and hence increased p53 activity on tumorigenesis and life span in mice. Here we report that mice with decreased levels of Mdm2 are resistant to tumor formation yet do not age prematurely, supporting the notion that Mdm2 is a promising target for cancer therapeutics.

Irradiation of mammalian cells with UV light results in a dose-dependent accumulation of the p53 tumorsuppressor gene product that is evident within 2 hr. UV treatment causes a dramatic increase in p53-specific transcriptional transactivation activity and an increase in expression of the p53-responsive gene mdm-2. UV-stimulated mdm-2 expression is not directy correlated with the level of p53 protein in a cell because mdm-2 induction is delayed at high UV doses even though p53 levels rise almost immediately. Cells lacking p53 protein do not respond to UV by increasing their expression of mdm-2. The delayed induction of mdm-2 at high UV doses suggests that, in addition to p53 protein levels, other factors contribute to the regulation of mdm-2 expression following UV treatment. The time of induction of mdm-2 in cells treated with UV light correlates with recovery of normal rates of DNA synthesis, presumably after DNA repair. These data indicate a possible role for mdm-2 in cell cycle progression.Mammalian cells respond to irradiation with UV light by transiently decreasing both RNA and DNA synthesis and by inducing expression of several genes whose products are thought to have protective effects against DNA damage (1). The regulation of these UV response genes appears to be mediated by several transcription factors which function after UV exposure (2). The p53 tumor-suppressor gene product is a transcription factor (3,4) that also appears to be involved in the response to UV light. The p53 protein levels increase due to the stabilization ofthis protein in both murine (5, 6) and human (7,8) cells treated with UV light. Although the role of p53 in the response to UV light has not been fully characterized, this tumor-suppressor protein has been shown to act as a cell cycle checkpoint in the response to y irradiation (9,10). fy irradiation induces both a G1 and a G2 phase-specific cell cycle block, and expression of wild-type p53 is necessary for the G1 but not the G2 block. The specific DNA-binding activity of p53 is increased after y irradiation and a DNA damage-inducible, growth arrest-specific gene, GADD45, has been shown to contain a p53 response element (10).Characterization of the role of p53 in the response to 'y irradiation led to the hypothesis that p53 acts as a cell cycle checkpoint, causing a delay in the G1 phase of the cycle during which damage is thought to be repaired (9, 10). It seemed likely that p53 might also act as a checkpoint in the response of cells to UV exposure. In addition, Zhan et al. (8) have recently shown that p53 transcriptional transactivation activity is increased in human cells exposed to UV light. Possible targets for p53 transcriptional transactivation activity in the UV response are the GADD45 gene, which was isolated as a UV response gene (11), and the mdm-2 gene. p53 and mdm-2 appear to form a feedback control loop: while p53The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" ...

Our data suggest that subsequent thrombo-occlusive events and death after focal cerebral ischemia associated with IgG aCL may occur sooner and more frequently with GPL > 40.