A peptide that binds and stabilizes p53 core domain: Chaperone strategy for rescue of oncogenic mutants

Friedler, Assaf; Hansson, Lars O.; Veprintsev, Dmitry B.; Freund, Stefan; Rippin, Thomas M; Nikolova, Penka V.; Proctor, Mark R.; Rüdiger, Stefan; Fersht, Alan R.

doi:10.1073/pnas.241629998

Cited by 241 publications

(202 citation statements)

References 23 publications

(30 reference statements)

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“…This unique property of ANKRD11 is similar to that reported for the small molecules and peptides, PRIMA-1 (Bykov et al, 2002) and CDB-3 (Friedler et al, 2002;Issaeva et al, 2003), which reportedly restore a native conformation to mutant p53. We also show that expression of the ANKRD11 ankyrin domain is sufficient to dissociate the p53-R175H Á p63 and p53-R175H Á p73 complexes (Figure 7).…”

Section: Input Igg Pab1620supporting

confidence: 83%

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

et al. 2011

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Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 'hotspot' mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53-p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.

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Section: Input Igg Pab1620supporting

confidence: 83%

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

et al. 2011

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“…How can new insights gained from the current study impact therapeutic strategies involving UV-induced skin carcinogenesis? While there appears to be a strong impetus to reactivate p53 functions in cancer cells, and such restoration may hold potential, caution is warranted based on the antiapoptotic role for p53 (Foster et al, 1999;Bykov et al, 2002;Friedler et al, 2002). Indeed, the paradoxical reduction in skin cancers occurring in p53 þ /À transgenic mice may parallel the current experience with human p53 siRNA treated KCs in which enhanced apoptosis following UV-light exposure was observed.…”

Section: Discussionmentioning

confidence: 94%

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

et al. 2005

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Ultraviolet (UV) light exposure is a common cause of epithelial-derived skin cancers, and the epidermal response to UV-light has been extensively studied using both mouse models and cultured human keratinocytes (KCs). Elimination of cells with UV-induced DNA damage via apoptosis provides a powerful mechanism to minimize retention or expansion of genetically abnormal cells. This cell editing function has largely been ascribed to the biological role of the p53 tumor suppressor gene, as mutations or deletions involving p53 have been linked to skin cancer development. Rather than introducing mutations, or using cells with complete loss of wild-type p53, we used an siRNA-based approach to knockdown, but not eliminate, p53 levels in primary cultures of human KCs followed by UV-irradiation. Surprisingly, when p53 levels were reduced by 50-80% the apoptosis induced by exposure to UV-light was accelerated and markedly enhanced (two-to three-fold) compared to control siRNA treated KCs. The p53 siRNA treated KCs were characterized by elevated E2F-1 levels accompanied by accelerated elimination of the Mcl-1 and Bcl-x L antiapoptotic proteins, as well as enhanced Bax oligomerization. Forced overexpression of either Mcl-1 or Bcl-x L reduced the UV-light enhanced apoptotic response in p53 siRNA treated KCs. We conclude that p53 not only can provide proapoptotic signals but also regulates a survival pathway influencing Mcl-1 and Bcl-x L levels. This overlooked survival function of p53 may explain previous paradoxical responses noted by investigators using p53 heterozygous and knockout mouse models, and opens up the possibility that not all liaisons within the cell involving p53 necessarily represent fatal attractions.

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“…Identification of molecules that target the altered expression of the ASPP family members, whereby ASPP1 and ASPP2 expression could be enhanced or iASPP expression reduced, will allow us to develop new therapeutic strategies to treat cancer. For instance, a nine amino-acid peptide derived from ASPP2 (CBP3) was found to bind to the p53 core domain and stabilise it in vitro (Friedler et al, 2002). CBP3 was capable of restoring the apoptotic function of mutant p53, thereby killing mutant p53-expressing cells.…”

Section: Resultsmentioning

confidence: 99%

ASPP: a new family of oncogenes and tumour suppressor genes

2007

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The apoptosis stimulating proteins of p53 (ASPP) family consists of three members, ASPP1, ASPP2 and iASPP. They bind to proteins that are key players in controlling apoptosis (p53, Bcl-2 and RelA/p65) and cell growth (APCL, PP1). So far, the best-known function of the ASPP family members is their ability to regulate the apoptotic function of p53 and its family members, p63 and p73. Biochemical and genetic evidence has shown that ASPP1 and ASPP2 activate, whereas iASPP inhibits, the apoptotic but not the cellcycle arrest function of p53. The p53 tumour suppressor gene, one of the most frequently mutated genes in human cancer, is capable of suppressing tumour growth through its ability to induce apoptosis or cell-cycle arrest. Thus, the ASPP family of proteins helps to determine how cells choose to die and may therefore be a novel target for cancer therapy.

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A peptide that binds and stabilizes p53 core domain: Chaperone strategy for rescue of oncogenic mutants

Cited by 241 publications

References 23 publications

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

ASPP: a new family of oncogenes and tumour suppressor genes

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