Mutant p53 proteins: Between loss and gain of function

Strano, Sabrina; Dell’Orso, Stefania; Mongiovi, Adriana Maria; Monti, Olimpia; Lapi, Eleonora; Agostino, Silvia Di; Fontemaggi, Giulia; Blandino, Giovanni

doi:10.1002/hed.20531

Cited by 49 publications

(44 citation statements)

References 88 publications

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“…Expression of certain p53 mutants confers cells with some resistance to genotoxic stress (2). It was therefore important to define whether PML contributes to this biological effect of mutant p53.…”

Section: Resultsmentioning

confidence: 99%

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Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53

Haupt

Agostino²,

Mizrahi³

et al. 2009

Cancer Research

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Mutations in the p53 tumor suppressor are the most common genetic events in human cancer. These mutations not only result in a loss of wild-type p53 activity, but can also lead to a gain of new oncogenic properties. Understanding how these gained functions are regulated is in its infancy. In this study, we show that the promyelocytic leukemia (PML) protein is an important regulator of mutant p53. We show that PML interacts with mutant p53. Importantly, PML enhances the transcriptional activity of mutant p53. Unexpectedly, PML is required for the proliferation and colony formation of cancer cells bearing mutant p53. Down-regulation of PML expression inhibits the growth of mutant p53-expressing cancer cells, predominantly by promoting cell cycle arrest. Our results suggest that the tumor suppression function of PML depends on the status of p53. In the context of mutant p53, PML enhances its cancer-promoting activities. [Cancer Res 2009;69(11):4818-26]

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Section: Resultsmentioning

confidence: 99%

“…Furthermore, mutant p53 may acquire distinct properties from its wild-type counterpart, referred to as a ''gain of function'' (GOF) phenomena (reviewed in ref. 2). The contribution of certain p53 mutations to chemotherapeutic drug resistance was shown in human cancer cells cultured in vitro (reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53

Haupt

Agostino²,

Mizrahi³

et al. 2009

Cancer Research

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“…Gain-of-function mut-p53 possesses tumor-promoting functions, such as the transcriptional activation of genes that promote various malignancy variables (14)(15)(16)(17). We found that PTEN restoration to glioblastoma cells harboring gain-of-function p53 mutations leads to induction of cell proliferation and inhibition of cell death possibly via inhibition of mut-p53 degradation by Mdm2 and direct stabilization of mut-p53 protein.…”

Section: Introductionmentioning

confidence: 85%

PTEN Has Tumor-Promoting Properties in the Setting of Gain-of-Function p53 Mutations

Guessous

Kwon

et al. 2008

Cancer Research

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We show, for the first time, that the tumor suppressor PTEN can have tumor-promoting properties. We show that PTEN acquires these unexpected properties by enhancing gainof-function mutant p53 (mut-p53) protein levels. We find that PTEN restoration to cells harboring mut-p53 leads to induction of G 1 -S cell cycle progression and cell proliferation and to inhibition of cell death. Conversely, PTEN inhibition in cells expressing wild-type PTEN and mut-p53 leads to inhibition of cell proliferation and inhibition of in vivo tumor growth. We show the dependency of the tumor-promoting effects of PTEN on mut-p53 by showing that knockdown of mut-p53 expression inhibits or reverses the tumor-promoting effects of PTEN. Mechanistically, we show that PTEN expression enhances mut-p53 protein levels via inhibition of mutp53 degradation by Mdm2 and possibly also via direct protein binding. These findings describe a novel function of PTEN and have important implications for experimental and therapeutic strategies that aim at manipulating PTEN or p53 in human tumors. They suggest that the mutational status of PTEN and p53 should be considered to achieve favorable therapeutic outcomes. The findings also provide an explanation for the low frequency of simultaneous mutations of PTEN and p53 in human cancer.

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“…The intermittent signal of ATM produces a rise in the ASPP concentration, so it will be a question of time for the cell to enter in apoptosis. This could explain why after a long period of time if the cell is not repaired, it dies (Zhang et al, 2009;Yoda et al, 2001;Robinson et al, 2008;Shreeram et al, 2006;Wang et al, 2007;Bergamaschi et al, 2004;Braithwaite, 2006;Green and Kroemer, 2009;Toledo and Wahl, 2006;Liu et al, 2005;Haupt et al,, 2006;Strano et al, 2006;Zhang et al, 2008).…”

Section: Medium Dna Damage Among Life and Deathmentioning

confidence: 99%