Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707
Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707
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DOI：
10.1128/mcb.23.13.4598-4610.2003
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发表时间：
2003-07-01
影响因子：
5.3
通讯作者：
Dimmeler, S
中科院分区：
文献类型：
--
作者：
Haendeler, J;Hoffmann, J;Dimmeler, S
端粒酶逆转录酶(TERT)的调控对细胞的增殖能力和生存起着重要作用。在这里，我们报告了外源性和内源性诱导的氧化应激导致内源性和过表达的人类TERT从细胞核移位到胞浆中。TERT通过核孔转运，这是一种对软霉素敏感且依赖Ran GTP酶的过程。在过氧化氢诱导的TERT核输出之前，第707位的TERT酪氨酸磷酸化，并被Src激酶家族抑制剂PP1阻止。氧化应激诱导的TERT核输出依赖于与RAN GTP酶的关联。相反，酪氨酸707的突变抑制了氧化应激诱导的磷酸化，并阻止了与RAN和TERT核输出的关联。此外，抑制707位的酪氨酸磷酸化增加了TERT的抗凋亡能力。综上所述，通过依赖酪氨酸磷酸化的TERT核输出来耗尽核TERT是调节TERT定位的一种新机制，它降低了TERT的抗凋亡活性。
The regulation of telomerase reverse transcriptase (TERT) plays an important role in the proliferative capacity and survival of cells. Here, we report that exogenously as well as endogenously induced oxidative stress leads to translocation of endogenous as well as overexpressed human TERT from the nucleus into the cytosol. TERT is transported through the nuclear pores in a leptomycin-sensitive and Ran GTPase-dependent process. H2O2-induced nuclear export of TERT is preceded by TERT tyrosine phosphorylation at position 707 and prevented by the Src kinase family inhibitor PP1. Oxidative stress-induced nuclear export of TERT depends on association with the Ran GTPase. In contrast, mutation of tyrosine 707 inhibits phosphorylation induced by oxidative stress and prevents association with Ran and nuclear export of TERT. Moreover, inhibition of tyrosine phosphorylation at 707 increases the antiapoptotic capacity of TERT. Taken together, depletion of nuclear TERT by tyrosine phosphorylation-dependent nuclear export of TERT is a novel mechanism for regulation of TERT localization, which reduces the antiapoptotic activity of TERT.