Gain-of-function p53 activates multiple signaling pathways to induce oncogenicity in lung cancer cells.

Abstract:

:Gain-of-function (GOF) mutants of p53 upregulate genes implicated in cell proliferation and oncogenesis. Here, we report that GOF p53 induces tumorigenicity through simultaneous activation of key oncogenic pathways including those controlling putative tumor-initiating cell functions. We determined that in cells expressing p53-R273H, GOF p53 simultaneously upregulates genes from multiple signaling pathways by recognizing promoters containing distinct transcription factor (TF) binding sites. Our analytical data support a model in which GOF p53 complexes with two TFs on the promoter-a mediator protein, Med17, and a histone acetyl transferase, activating histone acetylation-and enhances gene expression to signal cell proliferation and oncogenesis. Thus, therapeutic inhibition of one GOF p53-induced pathway would be insufficient to prevent tumor growth as the oncoprotein activates a multitude of parallel pathways. This discovery suggests enormous selection advantage for cancer cells with GOF p53 to induce oncogenic growth, highlighting the problems of cancer therapy.

journal_name

Mol Oncol

journal_title

Molecular oncology

authors

Vaughan CA,Singh S,Grossman SR,Windle B,Deb SP,Deb S

doi

10.1002/1878-0261.12068

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

696-711

issue

6

eissn

1574-7891

issn

1878-0261

journal_volume

11

pub_type

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