Mutant p53: One name, many proteins

Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Genes & development (Impact Factor: 12.64). 06/2012; 26(12):1268-86. DOI: 10.1101/gad.190678.112
Source: PubMed

ABSTRACT There is now strong evidence that mutation not only abrogates p53 tumor-suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function.

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    • "Although knowledge of the mechanisms of mutant p53 gainof-function remains incomplete, mutant p53 activity has been attributed to diverse mechanisms, including both transcriptional and post-transcriptional mechanisms through interactions with other cellular proteins [33] [64]. The most studied mutant p53 interacting proteins are the p53 family members, p63 and p73. "
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    ABSTRACT: MicroRNAs are potent regulators of gene expression and modulate multiple cellular processes including proliferation, differentiation and apoptosis. A number of microRNAs have been shown to be regulated by p53, the most frequently mutated gene in human cancer. It is has been demonstrated that some mutant p53 proteins not only lose tumor suppressor activity, but also acquire novel oncogenic functions that are independent of wild-type p53. In this review, we highlight recent evidences suggesting that some mutant p53 proteins regulate the expression of specific microRNAs to gain oncogenic functions and identify a gene network regulated by the microRNAs downstream of mutant p53.
    FEBS letters 04/2014; 588(16). DOI:10.1016/j.febslet.2014.03.054 · 3.34 Impact Factor
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    • "The differential interaction among p53 mutants and VRK1 can contribute to partly explain their differential effects. Differences in biological effects have already been associated to different p53 mutations [53] [59] [60], which may also be dependent on cell type and its interactome. The p53 mutants R175H and R273H appear to facilitate cell invasion by interaction Fig. 5. Connectivity map between VRK1 and proteins implicated in DNA-damage responses (DDR) and repair. "
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    ABSTRACT: DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1-p53 basal complex is an early-warning system for immediate cellular responses to DNA damage. VRK1physically interactswithp53byanti bait coimmunoprecipitation(1,2,3,4) VRK1physically interactswithp53bypull down(1,2,3).
    FEBS letters 01/2014; 588(5). DOI:10.1016/j.febslet.2014.01.040 · 3.34 Impact Factor
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    ABSTRACT: The Mdm2 oncoprotein promotes p53 ubiquitination and destruction. Yet, exact molecular mechanisms of Mdm2 destruction itself, under DNA damaging conditions, remain unclear. Recently, we identified SCFβ-TRCP as a novel E3 ligase that targets Mdm2 for ubiquitination and destruction in a Casein Kinase Iδ (CKIδ)-dependent manner. However, it remains elusive how the β-TRCP/CKIδ/Mdm2 signaling axis is regulated by DNA damage signals to govern p53 activity. Consistent with previous studies, we found that inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase, in turn, impaired DNA damage-induced Mdm2 destruction. Although phosphorylation of Mdm2 at Ser395 (an ATM phosphorylation site) facilitated Mdm2 interaction with β-TRCP, Ser395A-Mdm2 was degraded non-distinguishably from WT-Mdm2 by SCFβ-TRCP upon DNA damaging treatments. This indicates that in addition to phosphorylating Mdm2 at Ser395, ATM may govern Mdm2 stability through other unknown mechanisms. We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKIδ at two well-conserved S/TQ sites, which promotes CKIδ nuclear localization to increase CKIδ-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCFβ-TRCP. Our studies provide a molecular mechanism of how ATM could govern DNA damage-induced destruction of Mdm2 in part by phosphorylating both Mdm2 and CKIδ to modulate SCFβ-TRCP-mediated Mdm2 ubiquitination. Given the pivotal role of Mdm2 in the negative regulation of p53, this work will also provide a rationale for developing CKIδ or ATM agonists as anti-cancer agents.
    Oncotarget 09/2012; 3(9):1026-35. · 6.63 Impact Factor
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