mdm2 expression is induced by wild type p53 activity.

Abstract

We have recently characterized a 95 kDa protein, p95, which exhibits enhanced binding to temperature‐sensitive p53 (ts‐p53) when cells are shifted down to 32.5 degrees C, a temperature at which ts‐p53 possesses wild‐type (wt)‐like activities. In the present study we show that p95 is a product of the mdm2 putative proto‐oncogene. The enhanced complex formation of mdm2 with ts‐p53 in cells maintained at 32.5 degrees C is due to an elevation in total mdm2 protein levels following the temperature shift. We further demonstrate that the induction of mdm2 expression by t p53 activity is at the mRNA level. The induction occurs with very rapid kinetics and does not require de novo protein synthesis, suggesting a direct involvement of p53 in the process. Based on these data and on recent findings implicating p53 as a transcription factor, we suggest that the mdm2 gene is a target for activation by wt p53. In view of the ability of mdm2 to act as a specific antagonist of p53 activity, this induction process may serve to tightly autoregulate p53 activity in living cells.

Targeting gene expression to tumor cells with loss of wild-type p53 function

“…Among mtp53 constructs, we included four hot-spot mutants: 175r3h, 248arg3trp (248r3w), 249r3s, and 273r3h, which collectively account for nearly 30% of the mutations in human tumors. 21 As expected, neither suppression of the Hsp70 promoter activity nor transactivation of the GC3p53tk promoter were observed (Fig 2, A and B, columns 5-11). Analysis of protein extracts by Western blotting showed expression of the p53 constructs in transfected cells (Fig 2C).…”

Prognostic Significance of Survivin in Pediatric Acute Lymphoblastic Leukemia

“…Regulation of apoptosis is delicately balanced by signaling pathways between apoptosis-promoting factors such as p53 and caspases, and antiapoptotic factors such as Bcl-2 and MDM2 [3,4]. A group of apoptosis inhibitor molecules called inhibitor of apoptosis proteins (IAP) constitute a family of evolutionarily conserved apoptosis suppressors (n = 8 in humans), many of which function as endogenous inhibitors of caspases, one member of the IAP family is survivin [5].…”

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

“…Studies on Adenovirus E1A demonstrate that p53 stabilization is mediated by the activation of E2F-1, which in turn stimulates the transcription of the tumour suppressor p19 ARF gene . p19 ARF associates with and inhibits Mdm2 (Kamijo et al, 1998;Pomerantz et al, 1998;Stott et al, 1998;Zhang et al, 1998), which acts in a feedback loop to antagonize p53 function by direct binding (Barak et al, 1993;Wu et al, 1993). Mdm2 association with p53 inhibits p53 transcriptional activity (Momand et al, 1992;Oliner et al, 1993), induces p53 ubiquitination (Haupt et al, 1997;Honda et al, 1997;Kubbutat et al, 1997) and accelerates p53 nuclear export and its degradation in cytoplasmic proteosomes (Roth et al, 1998).…”