title: ERK1/2/MAPK pathway-dependent regulation of the telomeric factor TRF2.
abstract: Telomere stability is a hallmark of immortalized cells, including cancer cells. While the telomere length is maintained in most cases by the telomerase, the activity of a protein complex called Shelterin is required to protect telomeres against unsuitable activation of the DNA damage response pathway. Within this complex, telomeric repeat binding factor 2 (TRF2) plays an essential role by blocking the ataxia telangiectasia-mutated protein (ATM) signaling pathway at telomeres and preventing chromosome end fusion. We showed that TRF2 was phosphorylated in vitro and in vivo on serine 323 by extracellular signal-regulated kinase (ERK1/2) in both normal and cancer cells. Moreover, TRF2 and activated ERK1/2 unexpectedly interacted in the cytoplasm of tumor cells and human tumor tissues. The expression of non-phosphorylatable forms of TRF2 in melanoma cells induced the DNA damage response, leading to growth arrest and tumor reversion. These findings revealed that the telomere stability is under direct control of one of the major pro-oncogenic signaling pathways (RAS/RAF/MEK/ERK) via TRF2 phosphorylation.
authors.affiliation: Centre Scientifique de Monaco, Biomedical Department, MC-98000 Monaco, Principality of Monaco.
authors.forename: Vincent
authors.initials: V
authors.lastname: Picco
authors.affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coste
authors.affiliation: University of Nice, Sophia Antipolis, Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS UMR7284/INSERM U1081, Medical School, 06107 Nice, France.
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Giraud-Panis
authors.affiliation: Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Toufic
authors.initials: T
authors.lastname: Renno
authors.affiliation: University of Nice, Sophia Antipolis, Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS UMR7284/INSERM U1081, Medical School, 06107 Nice, France.|Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, 06200 Nice, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.affiliation: University of Nice, Sophia Antipolis, Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS UMR7284/INSERM U1081, Medical School, 06107 Nice, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D016615:Telomere / Q000502:physiology; D035341:Telomeric Repeat Binding Protein 2 / Q000502:physiology*
chemical_list: C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: DNA damage; MAP kinases; cancer; phosphorylation; telomere