Abstract
MDM2 is a short-lived protein that regulates p53 degradation. We report here that transient coexpression of MDM2 and several p53 hotspot mutants resulted in stabilization and increased expression of MDM2. Ectopic expression of the mutant p53(175H) allele by recombinant adenovirus infection or stable transfection also stabilized endogenous MDM2 in p53-null cells. A panel of human tumor cell lines expressing different endogenous mutant p53 alleles also contained stabilized nuclear MDM2 at elevated levels when compared with p53-null cells. MDM2 was present in complexes with mutant p53 in tumor cells, and stabilization of MDM2 required direct binding to mutant p53. These results reveal a novel property of mutant p53 and a unique feature of tumors with p53 missense mutations. Accumulation of stable MDM2 may contribute to tumorigenesis through its p53-independent transforming functions.
Highlights
The p53 tumor suppressor is a transcription factor that is mutated in over 50% of human tumors primarily because of missense mutations in the DNA binding domain [1]
Mutant p53 had no significant effect on the expression of cotransfected green fluorescent protein GFP (Fig. 1A), suggesting that the increase of MDM2 expression was not because of enhancement of transfection efficiency
The results described above demonstrate that expression of p53 core domain mutants in tumor cells causes stabilization of MDM2
Summary
The p53 tumor suppressor is a transcription factor that is mutated in over 50% of human tumors primarily because of missense mutations in the DNA binding domain [1]. A major consequence of p53 mutation is loss of its tumor suppressor function, maintenance of high level mutant p53 expression during tumor development suggests that it may have positive effects on cell proliferation. Mutational analysis suggests that amino acids 22 and 23 of p53, which are essential for transcription activation and MDM2 binding, are important for the gain-of-function phenotype of the 281G mutant [16]. MDM2 can interact with and inactivate the retinoblastoma tumor suppressor (pRb, Ref. 20) It can modulate the activity, stability, and apoptotic function of E2F1/ DP1 transcription factors [21,22,23]. Several experimental approaches demonstrate that overexpression of mutant p53 can prevent MDM2 degradation, resulting in the accumulation of MDM2 in tumor cells to moderate levels These results suggest a novel mechanism of MDM2 stabilization and accumulation
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