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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 up-regulates genes from multiple signaling pathways by recognizing promoters containing distinct transcription factor binding sites. Our analytical data support a model in which GOF p53 complexes with two transcription factors 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. This article is protected by copyright. All rights reserved.

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  • Authors+Show Affiliations

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    Department of Biochemistry & Molecular Biology.

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    Integrated Life Sciences Program.

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    Massey Cancer Center. Department of Internal Medicine, Division of Hematology, Oncology and Palliative Care.

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    Integrated Life Sciences Program. Massey Cancer Center. Philips Institute, Virginia Commonwealth University, Richmond, VA, 23298.

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    Department of Biochemistry & Molecular Biology. Integrated Life Sciences Program. Massey Cancer Center.

    Department of Biochemistry & Molecular Biology. Integrated Life Sciences Program. Massey Cancer Center.

    Source

    Molecular oncology : 2017 Apr 18 pg

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    28423230