scholarly journals Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis

2013 ◽  
Vol 20 (7) ◽  
pp. 898-909 ◽  
Author(s):  
W Hanel ◽  
N Marchenko ◽  
S Xu ◽  
S Xiaofeng Yu ◽  
W Weng ◽  
...  
Keyword(s):  
Mouse Models ◽  
Hot Spot ◽  
Mutant P53 ◽  
Gain Of Function ◽  
Differential Gain

scholarly journals Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 188 ◽  
Author(s):  
Ramona Schulz-Heddergott ◽  
Ute Moll
Keyword(s):  
Mouse Models ◽  
Therapeutic Target ◽  
Drug Target ◽  
Protein Targeting ◽  
Convincing Evidence ◽  
Malignant Progression ◽  
Mutant P53 ◽  
Specific Drug ◽  
Gain Of Function ◽  
Missense Mutant

p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to reduced survival in patients and mice. Notably, these oncogenic gain-of-function (GOF) missense mutant p53 proteins (mutp53) are constitutively and tumor-specific stabilised. This stabilisation is one key pre-requisite for their GOF and is largely due to mutp53 protection from the E3 ubiquitin ligases Mdm2 and CHIP by the HSP90/HDAC6 chaperone machinery. Recent mouse models provide convincing evidence that tumors with highly stabilized GOF mutp53 proteins depend on them for growth, maintenance, and metastasis, thus creating exploitable tumor-specific vulnerabilities that markedly increase lifespan if intercepted. This identifies mutp53 as a promising cancer-specific drug target. This review discusses direct mutp53 protein-targeting drug strategies that are currently being developed at various preclinical levels.

scholarly journals Mutant p53 Gain of Function in Two Mouse Models of Li-Fraumeni Syndrome

Cell ◽  
2004 ◽  
Vol 119 (6) ◽  
pp. 847-860 ◽  
Author(s):  
Kenneth P. Olive ◽  
David A. Tuveson ◽  
Zachary C. Ruhe ◽  
Bob Yin ◽  
Nicholas A. Willis ◽  
...  
Keyword(s):  
Mouse Models ◽  
Mutant P53 ◽  
Gain Of Function ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni

scholarly journals Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism

Oncotarget ◽  
2018 ◽  
Vol 9 (62) ◽  
pp. 32063-32080 ◽  
Author(s):  
Dawid Walerych ◽  
Magdalena Pruszko ◽  
Lukasz Zyla ◽  
Michalina Wezyk ◽  
Katarzyna Gaweda-Walerych ◽  
...  
Keyword(s):  
Hot Spot ◽  
Mutant P53 ◽  
Wild Type ◽  
Gain Of Function ◽  
Wild Type P53

scholarly journals Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity

2018 ◽  
Vol 39 (4) ◽  
Author(s):  
Leixiang Yang ◽  
Tanjing Song ◽  
Qian Cheng ◽  
Lihong Chen ◽  
Jiandong Chen
Keyword(s):  
Tumor Cells ◽  
Recent Work ◽  
Intramolecular Interaction ◽  
E3 Ligase ◽  
Mutant P53 ◽  
Wild Type ◽  
Gain Of Function ◽  
Core Domain ◽  
Acidic Domain ◽  
Wild Type P53

ABSTRACT Missense p53 mutants often accumulate in tumors and drive progression through gain of function. MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Here, we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity than wild-type p53. The mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme. An MDM2 construct with extra copies of the acidic domain is resistant to inhibition by mutant p53 and efficiently promotes mutant p53 ubiquitination and degradation. The results suggest that mutant p53 interferes with the intramolecular autoactivation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells.

scholarly journals Pontin, a novel interactor of mutant p53 that promotes mutant p53 gain of function

2015 ◽  
Vol 3 (2) ◽  
pp. e1076587
Author(s):  
Yuhan Zhao ◽  
Xuetian Yue ◽  
Wenwei Hu
Keyword(s):  
Mutant P53 ◽  
Gain Of Function

scholarly journals Pontin, a new mutant p53-binding protein, promotes gain-of-function of mutant p53

2015 ◽  
Vol 22 (11) ◽  
pp. 1824-1836 ◽  
Author(s):  
Y Zhao ◽  
C Zhang ◽  
X Yue ◽  
X Li ◽  
J Liu ◽  
...  
Keyword(s):  
Binding Protein ◽  
Mutant P53 ◽  
Gain Of Function

scholarly journals Mutant p53 Disrupts MCF-10A Cell Polarity in Three-dimensional Culture via Epithelial-to-mesenchymal Transitions

2011 ◽  
Vol 286 (18) ◽  
pp. 16218-16228 ◽  
Author(s):  
Yanhong Zhang ◽  
Wensheng Yan ◽  
Xinbin Chen
Keyword(s):  
Cell Polarity ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Three Dimensional ◽  
Mutant P53 ◽  
Wild Type ◽  
Gain Of Function ◽  
Three Dimensional Culture ◽  
Wild Type P53 ◽  
E Cadherin

Mutant p53 is not only deficient in tumor suppression but also acquires additional activity, called gain of function. Mutant p53 gain of function is recapitulated in knock-in mice that carry one null allele and one mutant allele of the p53 gene. These knock-in mice develop aggressive tumors compared with p53-null mice. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for cell survival and resistance to DNA damage. To further define mutant p53 gain of function, we used the MCF-10A three-dimensional model of mammary morphogenesis. MCF-10A cells in three-dimensional culture undergo a series of morphological changes and form polarized and growth-arrested spheroids with hollow lumen, which resembles normal glandular architectures in vivo. Here, we found that endogenous wild-type p53 in MCF-10A cells was not required for acinus formation, but knockdown of endogenous wild-type p53 (p53-KD) led to partial clearance of cells in the lumen due to decreased apoptosis. Consistent with this, p53-KD altered expression patterns of the cell adhesion molecule E-cadherin, the cytoskeletal marker β-catenin, and the extracellular matrix protein laminin V. We also found that ectopic expression of the mutant G245S led to a phenotype similar to p53-KD, whereas a combination of ectopic expression of siRNA-resistant G245S with p53-KD led to a less cleared lumen. In contrast, ectopic expression of mutant R248W, R175H, and R273H disrupted normal acinus architectures with filled lumen and led to formation of irregular and multiacinus structures regardless of p53-KD. In addition, these mutants altered normal expression patterns and/or levels of E-cadherin, β-catenin, laminin V, and tight junction marker ZO-1. Furthermore, epithelial-to-mesenchymal transitions (EMT) markers, Snail, Slug, and Twist, were highly induced by mutant p53 and/or p53-KD. Together, we postulate that EMT represents a mutant p53 gain of function and mutant p53 alters cell polarity via EMT.

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