title: TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation.
abstract: The mechanism of telomerase re-activation in cancer had remained elusive until the discovery of frequent mutations in the promoter of the TERT gene that encodes the catalytic reverse transcriptase subunit of telomerase. We investigated the regulation of TERT expression in melanoma cell lines and our results show that promoter mutations render TERT expression dependent on MAPK activation due to oncogenic BRAF or NRAS mutations. Mutations in the TERT promoter create binding sites for ETS transcription factors. ETS1, expressed in melanoma cell lines, undergoes activating phosphorylation by ERK at Thr38 residue as a consequence of constitutively activated MAPK pathway. We demonstrate that ETS1 binds on the mutated TERT promoter leading to the re-expression of the gene. The inhibition of ETS1 resulted in reduced TERT expression. We provide evidence that the TERT promoter mutations provide a direct link between TERT expression and MAPK pathway activation due to BRAF or NRAS mutations via the transcription factor ETS1.
authors.affiliation: INSERM, U976, Skin Research Centre, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.|Department of Internal Medicine, School of Medicine Sciences, State University of Campinas (UNICAMP), 13083-970, Campinas, SP, Brazil.
authors.forename: Andrelou F
authors.initials: AF
authors.lastname: Vallarelli
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: P Sivaramakrishna
authors.initials: PS
authors.lastname: Rachakonda
authors.affiliation: INSERM, U976, Skin Research Centre, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: André
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Heidenreich
authors.affiliation: INSERM, U976, Skin Research Centre, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Riffaud
authors.affiliation: INSERM, U976, Skin Research Centre, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Bensussan
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: INSERM, U976, Skin Research Centre, Hôpital Saint-Louis, Paris, F-75010, France.|Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, F-75010, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumaz
mesh_terms: D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D050784:Proto-Oncogene Protein c-ets-1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019098:Telomerase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF; ETS1; MAPK pathway; melanoma; telomerase