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Gain-of-function hot spot mutant p53R248Q regulation of integrin/FAK/ERK signaling in esophageal squamous cell carcinoma.


ABSTRACT:

Purpose

TP53, encoding the protein p53, is among the most frequently mutated genes in all cancers. A high frequency of 60 - 90% mutations is seen in esophageal squamous cell carcinoma (ESCC) patients. Certain p53 mutants show gain-of-function (GoF) oncogenic features unrelated to its wild type functions.

Methods

This study functionally characterized a panel of p53 mutants in individual ESCC cell lines and assayed for GoF oncogenic properties.

Results

The ESCC cell line with endogenous p53R248Q expression showed suppressed tumor growth in an immunocompromised mouse model and suppressed colony growth in in vitro three-dimensional culture, when depleted of the endogenous p53 protein expression. This suppression is accompanied by suppressed cell cycle progression, along with reduced integrin expression and decreased focal adhesion kinase and extracellular-regulated protein kinase signaling and can be compensated by expression of a constitutively active mitogen-activated protein. P53R248Q enhances cell proliferation upon glutamine deprivation, as compared to other non-GoF mutants.

Conclusions

In summary, study of the functional contributions of endogenous p53 mutants identified a novel GoF mechanism through which a specific p53 mutant exerts oncogenic features and contributes to ESCC tumorigenesis.

SUBMITTER: Yu VZ 

PROVIDER: S-EPMC7744772 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Gain-of-function hot spot mutant p53<sup>R248Q</sup> regulation of integrin/FAK/ERK signaling in esophageal squamous cell carcinoma.

Yu Valen Zhuoyou VZ   So Shan Shan SS   Lung Maria Li ML  

Translational oncology 20201211 1


<h4>Purpose</h4>TP53, encoding the protein p53, is among the most frequently mutated genes in all cancers. A high frequency of 60 - 90% mutations is seen in esophageal squamous cell carcinoma (ESCC) patients. Certain p53 mutants show gain-of-function (GoF) oncogenic features unrelated to its wild type functions.<h4>Methods</h4>This study functionally characterized a panel of p53 mutants in individual ESCC cell lines and assayed for GoF oncogenic properties.<h4>Results</h4>The ESCC cell line with  ...[more]

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