Involvement of 14-3-3 proteins in nuclear localization of telomerase

Maintenance of telomeres is implicated in chromosome stabilization and cell immortalization, Telomerase, which catalyzes de novo synthesis of telomere s, is activated in germ cells and most cancers. Telomerase activity is regu lated by gene expression for its catalytic subunit, TERT, whereas several l ines of evidence have suggested a post-translational regulation of telomera se activity. Here we identify the 14-3-3 signaling proteins as human TERT ( hTERT)-binding partners. A dominant-negative 14-3-3 redistributed hTERT, wh ich was normally predominant in the nucleus, into the cytoplasm, Consistent with this observation, hTERT-3A, a mutant that could not bind 14-3-3, was localized into the cytoplasm, Leptomycin B, an inhibitor of CRM1/exportin 1 -mediated nuclear export, or disruption of a nuclear export signal (NES)-li ke motif located just upstream of the 14-3-3 binding site in hTERT impaired the cytoplasmic localization of hTERT, Compared with mild-type hTERT, hTER T-3A increased its association with CRM1, 14-3-3 binding was not required f or telomerase activity either in vitro or in cell extracts. These observati ons suggest that 14-3-3 enhances nuclear localization of TERT by inhibiting the CRM1 binding to the TERT NES-like motif.