Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer
Open Access
- 8 February 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 9 (1), 1-13
- https://doi.org/10.1038/s41467-018-03033-1
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.This publication has 57 references indexed in Scilit:
- Highly Recurrent TERT Promoter Mutations in Human MelanomaScience, 2013
- Alternatively Spliced Telomerase Reverse Transcriptase Variants Lacking Telomerase Activity Stimulate Cell ProliferationMolecular and Cellular Biology, 2012
- The Prognostic Value of BRAF Mutation in Colorectal Cancer and Melanoma: A Systematic Review and Meta-AnalysisPLOS ONE, 2012
- The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective mannerProceedings of the National Academy of Sciences of the United States of America, 2010
- PLX4032, a selective BRAF V600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF WT melanoma cellsPigment Cell & Melanoma Research, 2010
- An RNA-dependent RNA polymerase formed by TERT and the RMRP RNANature, 2009
- TERT Promotes Epithelial Proliferation through Transcriptional Control of a Myc- and Wnt-Related Developmental ProgramPLoS Genetics, 2008
- Protocol for the fast chromatin immunoprecipitation (ChIP) methodNature Protocols, 2006
- Mutations of the BRAF gene in human cancerNature, 2002
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001