Structural Distortion of p53 by the Mutation R249S and its Rescue by a Designed Peptide: Implications for “Mutant Conformation”

Friedler, Assaf; DeDecker, Brian S.; Freund, Stefan; Blair, Caroline M.; Rüdiger, Stefan; Fersht, Alan R.

doi:10.1016/j.jmb.2003.12.005

Cited by 70 publications

(59 citation statements)

References 21 publications

(38 reference statements)

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“…Altogether, the data suggest that the multichaperone complex of Hsc/p70-Hdj-Hsp90 forms on mutant p53 in an attempt to restore its active conformation in a manner similar to the heat-inactivated WT p53. However, its efficiency is limited because of the inherent instability caused by critical residue changes in p53, such as R249S (Friedler et al, 2004). We postulate that the stabilization of tumorigenic mutant p53 by molecular chaperones in vivo is a side effect of such attempts to restore p53 activity, which results in the stable binding of stalled chaperones to a mutant p53.…”

Section: Discussionmentioning

confidence: 99%

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

et al. 2009

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p53 as an unstable protein in vitro likely requires stabilizing factors to act as a tumor suppressor in vivo. Here, we show that in human cells transfected with wildtype (WT) p53, Hsp90 and Hsp70 molecular chaperones maintain the p53 native conformation under heat-shock conditions (42 1C) as well as assist p53 refolding at 37 1C, during the recovery from heat shock. We also show that the interaction of WT p53 with WAF1 promoter in cells is sensitive to Hsp70 and Hsp90 inhibition already at 37 1C and further decreased on heat shock. The influence of chaperones on p53 binding to the WAF1 promoter sequence has been confirmed in vitro, using highly purified proteins. Hsp90 stabilizes the binding of p53 to the promoter sequence at 37 1C, whereas under heat-shock conditions the requirement for the Hsp70-Hsp40 system and its cooperation with Hsp90 increases. Hop co-chaperone additionally stimulates these reactions. Interestingly, the combined Hsp90 and Hsp70-Hsp40 allow for a limited in vitro restoration of the DNA-binding activity by the p53 oncogenic variant R249S and affect its conformation in cells. Our results indicate for the first time that, especially under stress conditions, not only Hsp90 but also Hsp70 is required for the chaperoning of WT and R249S p53.

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Section: Discussionmentioning

confidence: 99%

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

et al. 2009

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“…Structural classes of p53 core domain cancer mutants A first indication that common p53 cancer mutants exhibit characteristic local structural changes came from heteronuclear single quantum correlation NMR spectroscopy studies (Wong et al, 1999;Friedler et al, 2004). Using the stabilized T-p53C variant, the finer details of the structural effects of numerous oncogenic mutations have been elucidated recently by X-ray crystallography (Joerger et al, 2005.…”

Section: Implications For the Analysis Of Antibody-binding Studiesmentioning

confidence: 99%

Structure–function–rescue: the diverse nature of common p53 cancer mutants

2007

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The tumor suppressor protein p53 is inactivated by mutation in about half of all human cancers. Most mutations are located in the DNA-binding domain of the protein. It is, therefore, important to understand the structure of p53 and how it responds to mutation, so as to predict the phenotypic response and cancer prognosis. In this review, we present recent structural and systematic functional data that elucidate the molecular basis of how p53 is inactivated by different types of cancer mutation. Intriguingly, common cancer mutants exhibit a variety of distinct local structural changes, while the overall structural scaffold is largely preserved. The diverse structural and energetic response to mutation determines: (i) the folding state of a particular mutant under physiological conditions; (ii) its affinity for the various p53 target DNA sequences; and (iii) its protein-protein interactions both within the p53 tetramer and with a multitude of regulatory proteins. Further, the structural details of individual mutants provide the basis for the design of specific and generic drugs for cancer therapy purposes. In combination with studies on second-site suppressor mutations, it appears that some mutants are ideal rescue candidates, whereas for others simple pharmacological rescue by small molecule drugs may not be successful.

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“…This is the case, for example, for p53 Ser249 (Serine to Arginine at codon 249), a mutant that commonly occurs in hepatocellular carcinoma in some parts of the world. 27 Yet, in intact cells, these mutants show a complete disruption of wild type structure with loss of DNA binding activity. This severe phenotype may result from the fact that, in vivo, imperfect folding exposes thiols in a way that favors oxidation, with formation of cross-links that prevent the mutant to revert to wild type form even if energetic conditions may allow this conformation.…”

Section: Redox Regulation Of Mutant P53mentioning

confidence: 99%

Mutant p53 rescue and modulation of p53 redox state

Bykov

Lambert²,

Hainaut³

et al. 2009

Cell Cycle

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The p53 tumor suppressor is a key regulator of cell growth and survival upon various forms of cellular stress. p53 is a redoxregulated transcription factor that binds specifically to DNA and activates transcription of target genes. The core domain of p53 holds a zinc atom that protects p53 from oxidation and is critical for DNA binding. A large fraction of human tumors carry p53 mutation, allowing evasion of apoptosis and tumor progression. Restoration of wild type p53 expression triggers rapid elimination of tumors in vivo. This makes mutant p53 an attractive target for novel cancer therapy. Small molecules have been identified that reactivate mutant p53 and induce apoptosis in tumor cells. Interestingly, several of these compounds share the ability to target thiols and affect the redox state of p53, indicating that this is critical for mutant p53 rescue. The identification of a common chemical activity among mutant p53-targeting compounds will facilitate the design of even more potent and selective mutant p53-targeting drugs for improved cancer therapy in the future.

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Structural Distortion of p53 by the Mutation R249S and its Rescue by a Designed Peptide: Implications for “Mutant Conformation”

Cited by 70 publications

References 21 publications

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

Structure–function–rescue: the diverse nature of common p53 cancer mutants

Mutant p53 rescue and modulation of p53 redox state

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