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Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer

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  • Rengyun Liu

    (John Hopkins University School of Medicine)

  • Tao Zhang

    (John Hopkins University School of Medicine)

  • Guangwu Zhu

    (John Hopkins University School of Medicine)

  • Mingzhao Xing

    (John Hopkins University School of Medicine)

Abstract

The unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations are widely found to be a robust genetic background promoting human cancer aggressiveness, but the mechanism is unclear. Here, we demonstrate that the BRAF V600E/MAP kinase pathway phosphorylates and activates FOS, which in turn acts as a transcription factor to bind and activate the GABPB promoter, increasing GABPB expression and driving formation of GABPA-GABPB complex; the latter selectively binds and activates mutant TERT promoter, upregulating TERT expression. Elevated TERT functions as a strong oncoprotein, robustly promoting aggressive behaviors of cancer cells and tumor development. We thus identify a molecular mechanism for the activation of mutant TERT by the BRAF V600E/MAP kinase pathway, in which FOS as a transcriptional factor of GABPB promoter plays a key role in functionally bridging the two oncogenes in cooperatively promoting oncogenesis, providing important cancer biological and clinical implications.

Suggested Citation

  • Rengyun Liu & Tao Zhang & Guangwu Zhu & Mingzhao Xing, 2018. "Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03033-1
    DOI: 10.1038/s41467-018-03033-1
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    Cited by:

    1. Carter J. Barger & Abigail K. Suwala & Katarzyna M. Soczek & Albert S. Wang & Min Y. Kim & Chibo Hong & Jennifer A. Doudna & Susan M. Chang & Joanna J. Phillips & David A. Solomon & Joseph F. Costello, 2022. "Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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