Picco Vincent, Coste Isabelle, Giraud-Panis Marie-Josèphe, Renno Toufic, Gilson Eric, Pagès Gilles
Centre Scientifique de Monaco, Biomedical Department, MC-98000 Monaco, Principality of Monaco.
Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
Oncotarget. 2016 Jul 19;7(29):46615-46627. doi: 10.18632/oncotarget.10316.
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.
端粒稳定性是永生化细胞（包括癌细胞）的一个标志。虽然在大多数情况下端粒长度由端粒酶维持，但需要一种名为遮蔽蛋白的蛋白质复合物的活性来保护端粒免受DNA损伤反应途径的不适当激活。在这个复合物中，端粒重复序列结合因子2（TRF2）通过在端粒处阻断共济失调毛细血管扩张症突变蛋白（ATM）信号通路并防止染色体末端融合发挥重要作用。我们发现，在正常细胞和癌细胞中，细胞外信号调节激酶（ERK1/2）都会在体外和体内使TRF2的丝氨酸323位点发生磷酸化。此外，TRF2与活化的ERK1/2在肿瘤细胞和人类肿瘤组织的细胞质中意外地相互作用。在黑色素瘤细胞中表达不可磷酸化形式的TRF2会诱导DNA损伤反应，导致生长停滞和肿瘤逆转。这些发现表明，端粒稳定性通过TRF2磷酸化受到主要促癌信号通路之一（RAS/RAF/MEK/ERK）的直接控制。
