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PMID: 12808100 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707.

Molecular and cellular biology ·Vol. 23 ·No. 13 ·2003-07-00 ·Pages 4598-610

Haendeler J, Hoffmann J, Brandes RP, Zeiher AM, Dimmeler S

Abstract

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. H(2)O(2)-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.

MeSH Terms
Active Transport, Cell Nucleus Apoptosis Cell Line Cell Nucleus/enzymology,metabolism Cell Separation Cloning, Molecular Cytosol/enzymology,metabolism DNA-Binding Proteins/metabolism Flow Cytometry Humans Hydrogen Peroxide/pharmacology Immunoblotting Microscopy, Fluorescence Oxidative Stress Phosphorylation Plant Proteins/metabolism Plasmids/metabolism Precipitin Tests Protein Transport Telomerase/metabolism Time Factors Tyrosine/metabolism ran GTP-Binding Protein/metabolism src-Family Kinases/metabolism
Chemicals
DNA-Binding Proteins PP1 protein, Physcomitrella patens Plant Proteins Tyrosine Hydrogen Peroxide src-Family Kinases TERT protein, human Telomerase ran GTP-Binding Protein
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Haendeler Judith
Molecular Cardiology, Department of Internal Medicine IV. Department of Physiology, University of Frankfurt, Frankfurt, Germany.
Hoffmann Jörg
Brandes Ralf P
Zeiher Andreas M
Dimmeler Stefanie
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.13.4598-4610.2003
Published
2003-07-00
Pages
4598-610
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC164856
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.23.13.4598-4610.2003 PMC Full Text View journal details
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