Mutant p53 proteins: Between loss and gain of function

Head & Neck ◽  
2007 ◽  
Vol 29 (5) ◽  
pp. 488-496 ◽  
Author(s):  
Sabrina Strano ◽  
Stefania Dell'Orso ◽  
Adriana Maria Mongiovi ◽  
Olimpia Monti ◽  
Eleonora Lapi ◽  
...  
Keyword(s):  
Mutant P53 ◽  
Gain Of Function

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.

scholarly journals Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

2017 ◽  
Vol 429 (11) ◽  
pp. 1595-1606 ◽  
Author(s):  
Xuetian Yue ◽  
Yuhan Zhao ◽  
Yang Xu ◽  
Min Zheng ◽  
Zhaohui Feng ◽  
...  
Keyword(s):  
Mutant P53 ◽  
Gain Of Function

scholarly journals Mutant p53 gain of function: repression of CD95(Fas/APO-1) gene expression by tumor-associated p53 mutants

Oncogene ◽  
2003 ◽  
Vol 22 (36) ◽  
pp. 5667-5676 ◽  
Author(s):  
Amir Zalcenstein ◽  
Perry Stambolsky ◽  
Lilach Weisz ◽  
Martina Müller ◽  
David Wallach ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mutant P53 ◽  
Gain Of Function
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