ERK1/2/MAPK pathway-dependent regulation of the telomeric factor TRF2

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 pathwa...

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Bibliographic Details
Published in:Oncotarget 2016-07, Vol.7 (29), p.46615-46627
Main Authors: Picco, Vincent, Coste, Isabelle, Giraud-Panis, Marie-Josèphe, Renno, Toufic, Gilson, Eric, Pagès, Gilles
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cancer
Cell Line
Cellular Biology
Extracellular Signal-Regulated MAP Kinases - physiology
Female
Humans
Life Sciences
MAP Kinase Signaling System - physiology
Mice
Phosphorylation
Research Paper
Telomere - physiology
Telomeric Repeat Binding Protein 2 - physiology
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.10316