Mutant p53 partners in crime

Kim, Michael P.; Lozano, Guillermina

doi:10.1038/cdd.2017.185

Cited by 246 publications

(239 citation statements)

References 39 publications

(61 reference statements)

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“…In support of this, mutant frequency was found to directly correlate with loss of transactivation function (Kato et al, 2003). The preferential selection of missense mutants together with their excessive stabilization therefore points at additional mechanisms that promote tumor development beyond a mere loss of DNA binding activity: Missense mutants exhibit dominant-negative effects on remaining wild-type p53 and display neomorphic properties thatlike an oncogene-actively drive tumor development to a metastatic and drug-resistant state (Freed-Pastor & Prives, 2012;Muller & Vousden, 2014;Kim & Lozano, 2018;Stiewe & Haran, 2018). Furthermore, missense mutants are unstable in normal unstressed cells, but become constitutively stabilized in tumors by Hsp90 which protects mutant p53 from degradation by Mdm2 and CHIP (Terzian et al, 2008;Alexandrova et al, 2015).…”

Section: Introductionmentioning

confidence: 90%

Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

et al. 2019

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Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53−/− mice. Surprisingly, stabilization of p53R178E in Mdm2−/− mice nevertheless triggers extensive apoptosis, indicative of residual wild‐type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E;Mdm2−/− embryos, it proves insufficient for suppression of spontaneous and oncogene‐driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53−/− mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53−/− ones, resulting in enhanced eradication of p53‐mutated tumor cells. Together, this provides genetic proof‐of‐principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.

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Section: Introductionmentioning

confidence: 90%

Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

et al. 2019

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“…The addiction of tumors to mutant p53 was demonstrated in the mutant TP53 knock-in mice, as the tamoxifen-induced mutant p53 ablation resulted in reduction of tumor growth, induction of apoptosis, and tumor regression, leading to 37% increase in animal survival (Alexandrova et al, 2015). It is believed that “gain of function” characteristics of the mutant p53 could be achieved via one of the two major mechanisms: a mutation conferring ability to transactivate the completely new set of genes (possibly via interaction with other transcription factors and chromatin remodeling proteins) and/or the interaction with other cellular proteins/signaling pathways (Freed-Pastor & Prives, 2012; Kim & Lozano, 2018). Precise details of both of these mechanisms will be dictated by the cell type and context and may be rather dynamic.…”

Section: Mutant P53 Functionmentioning

confidence: 99%

Ceramide Signaling and p53 Pathways

Jeffries¹,

Krupenko

2018

Advances in Cancer Research

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Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance. This regulation, however, can be pro-death or pro-survival depending on cancer type, the balance between ceramide species, the rate of their synthesis and utilization, and the availability of a specific array of downstream targets. This chapter highlights the central role of ceramide in sphingolipid metabolism, its role in cancer, specific effectors in ceramide pathways controlled by p53, and coregulation of ceramide and p53 signaling. We discuss the recent studies, which underscore the function of p53 in the regulation of ceramide pathways and the reciprocal regulation of p53 by ceramide. This complex relationship is based on several molecular mechanisms including the p53-dependent transcriptional regulation of enzymes in sphingolipid pathways, the activation of mutant p53 through ceramide-mediated alternative splicing, as well as modulation of the p53 function through direct and indirect effects on p53 coregulators and downstream targets. Further insight into the connections between ceramide and p53 will allow simultaneous targeting of the two pathways with a potential to yield more efficient anticancer therapeutics.

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“…Mouse modeling of such mutants places them in two classes based upon the tumorigenesis phenotype (Kim & Lozano, 2018;Sabapathy & Lane, 2018). The majority of such genetic alterations block the sequencespecific binding of p53, rendering the protein transcriptionally dead.…”

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confidence: 99%

p53 defies convention again: a p53 mutant that has lost tumor suppression but still can kill

Manfredi

2019

The EMBO Journal

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Loss of tumor suppression by the p53 protein involves altered or abrogated transcriptional activity resulting in a failure to mediate wild‐type cellular responses including cell cycle arrest, senescence, and apoptosis. Timofeev et al (2019) make the fascinating finding that a novel p53 cooperativity mutation devoid of DNA binding results in no tumor suppression but surprising retention of an apoptotic response to chemotherapy and other treatments. This shows a need for rethinking how mutant p53‐driven tumors are treated in the clinic.

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Mutant p53 partners in crime

Cited by 246 publications

References 39 publications

Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

Ceramide Signaling and p53 Pathways

p53 defies convention again: a p53 mutant that has lost tumor suppression but still can kill

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