Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated<i>TP53</i>and MDM2 up-regulation

Tracz-Gaszewska, Zuzanna; Klimczak, Marta; Biecek, Przemysław; Herok, Marcin; Kosiński, Marcin; Olszewski, Maciej B.; Czerwińska, Patrycja; Wiech, Milena; Wiznerowicz, Maciej; Żylicz, Alicja; Żylicz, Maciej; Wawrzynów, Bartosz

doi:10.18632/oncotarget.18899

Cited by 30 publications

(33 citation statements)

References 110 publications

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“…Moreover, CTM restores MDM2’s ability to induce mutp53 degradation. Additionally, Tracz-Gaszewska et al [100] observe that DNAJB1 and HSP70 facilitate binding of mutp53 (V143A, R158L, R175H, Y220C, G245S, D281G, R282W) to TAp73α. Another HSP40 member that plays a role in stabilization of mutp53 is DNAJA1.…”

Section: Molecular Chaperonesmentioning

confidence: 99%

Regulators of Oncogenic Mutant TP53 Gain of Function

Yamamoto

Iwakuma

2018

Cancers

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The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin ligases, and molecular chaperones, as well as a single nucleotide polymorphism (SNP) and dimer-forming mutations in mutp53.

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Section: Molecular Chaperonesmentioning

confidence: 99%

Regulators of Oncogenic Mutant TP53 Gain of Function

Yamamoto

Iwakuma

2018

Cancers

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“…This results in a loss of p73-mediated transcription and a gain in p63-mediated transcription [46,57]. Interestingly, a closer examination of the mutant p53-p73 complex further revealed that other HSP family members can also interact with the complex and that MDM2 can replace the HSP proteins to form a more stable complex and potentiate chemoresistance [58].…”

Section: Functional Consequences and Binding Partners Of Mutant P53-tmentioning

confidence: 99%

The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer

Hall

Müller

2019

IJMS

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The p53 family of proteins has grown substantially over the last 40 years. It started with p53, then p63, p73, isoforms and mutants of these proteins. The function of p53 as a tumour suppressor has been thoroughly investigated, but the functions of all isoforms and mutants and the interplay between them are still poorly understood. Mutant p53 proteins lose p53 function, display dominant-negative (DN) activity and display gain-of-function (GOF) to varying degrees. GOF was originally attributed to mutant p53′s inhibitory function over the p53 family members p63 and p73. It has become apparent that this is not the only way in which mutant p53 operates as a large number of transcription factors that are not related to p53 are activated on mutant p53 binding. This raises the question to what extent mutant p53 binding to p63 and p73 plays a role in mutant p53 GOF. In this review, we discuss the literature around the interaction between mutant p53 and family members, including other binding partners, the functional consequences and potential therapeutics.

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“…Moreover, it was shown recently that HSPs are involved in the evolution of cancer cells resulting in tumor heterogeneity. Such evolution could be accelerated by the chemotherapy and could lead to the acquisition of chemoresistance 11,21,22 . In contrast, some research has shown that reduced expression of HSPs is associated with poor prognosis in cancer patients 23,24 .…”

Section: Introductionmentioning

confidence: 99%

Heat shock proteins create a signature to predict the clinical outcome in breast cancer

Klimczak

Biecek

Żylicz

et al. 2019

Sci Rep

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Utilizing The Cancer Genome Atlas (TCGA) and KM plotter databases we identified six heat shock proteins associated with survival of breast cancer patients. The survival curves of samples with high and low expression of heat shock genes were compared by log-rank test (Mantel-Haenszel). Interestingly, patients overexpressing two identified HSPs – HSPA2 and DNAJC20 exhibited longer survival, whereas overexpression of other four HSPs – HSP90AA1, CCT1, CCT2, CCT6A resulted in unfavorable prognosis for breast cancer patients. We explored correlations between expression level of HSPs and clinicopathological features including tumor grade, tumor size, number of lymph nodes involved and hormone receptor status. Additionally, we identified a novel signature with the potential to serve as a prognostic model for breast cancer. Using univariate Cox regression analysis followed by multivariate Cox regression analysis, we built a risk score formula comprising prognostic HSPs (HSPA2, DNAJC20, HSP90AA1, CCT1, CCT2) and tumor stage to identify high-risk and low-risk cases. Finally, we analyzed the association of six prognostic HSP expression with survival of patients suffering from other types of cancer than breast cancer. We revealed that depending on cancer type, each of the six analyzed HSPs can act both as a positive, as well as a negative regulator of cancer development. Our study demonstrates a novel HSP signature for the outcome prediction of breast cancer patients and provides a new insight into ambiguous role of these proteins in cancer development.

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Molecular chaperones in the acquisition of cancer cell chemoresistance with mutatedTP53and MDM2 up-regulation

Abstract: Keywords: apoptosis, heat shock protein (HSP), mutant p53 gain-of-function, mouse double minute 2 homolog (MDM2),

Cited by 30 publications

References 110 publications

Regulators of Oncogenic Mutant TP53 Gain of Function

Regulators of Oncogenic Mutant TP53 Gain of Function

The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer

Heat shock proteins create a signature to predict the clinical outcome in breast cancer

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