Chromatin dysregulation by mutant p53.

Neil T Pfister,Carol Prives

doi:10.18632/oncotarget.7922

Abstract

The TP53 gene, which encodes a DNA sequence-dependent transcriptional regulator, is arguably the most frequently mutated gene in human cancer. Whereas wild-type p53 is restricted to its cognate DNA binding sites, mutant p53 (via mutation in the DNA binding domain) is no longer constrained to specific genomic sites. Mutant p53 proteins therefore cannot effectively mediate wild-type p53 tumor suppressive transcriptional programs, thereby enabling permissive tumor growth. Nevertheless, missense mutant forms of p53 can promiscuously alter the transcriptome of the cells they inhabit through association with transcription factors and other chromatin regulators. A global mechanism that could explain mutant p53- dependent gene expression changes would be a useful step in elucidating mutant p53 gain of oncogenic function.

Highlights

The TP53 gene, which encodes a DNA sequencedependent transcriptional regulator, is arguably the most frequently mutated gene in human cancer
In a recent issue of Genes & Development, we reported that mutant p53 stimulates expression of the VEGFR2 receptor tyrosine kinase (RTK), thereby stimulating oncogenic growth and malignant characteristics of breast cancer cells [1]
We further showed that mutant p53 functions with SWI/SNF to mediate >40% of mutant p53-dependent gene expression changes, providing the first evidence that mutant p53 influences promoter conformation and causes global gene expression changes through cooperation with a chromatin remodeling complex [1]

Summary

Introduction

The TP53 gene, which encodes a DNA sequencedependent transcriptional regulator, is arguably the most frequently mutated gene in human cancer. In a recent issue of Genes & Development, we reported that mutant p53 stimulates expression of the VEGFR2 receptor tyrosine kinase (RTK), thereby stimulating oncogenic growth and malignant characteristics of breast cancer cells [1]. Augmented transcription of VEGFR2 was shown to be the result of mutant p53 association with the SWI/SNF chromatin remodeling complex at the VEGFR2 promoter to enhance SWI/SNF-dependent chromatin remodeling.

Results

Conclusion