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 telomeres, is activated in germ cells and most cancers. Telomerase activity is regulated by gene expression for its catalytic subunit, TERT, whereas several lines of evidence have suggested a post-translational regulation of telomerase activity. Here we identify the 14-3-3 signaling proteins as human TERT (hTERT)-binding partners. A dominant-negative 14-3-3 redistributed hTERT, which 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)-like motif located just upstream of the 14-3-3 binding site in hTERT impaired the cytoplasmic localization of hTERT. Compared with wild-type hTERT, hTERT-3A increased its association with CRM1. 14-3-3 binding was not required for telomerase activity either in vitro or in cell extracts. These observations suggest that 14-3-3 enhances nuclear localization of TERT by inhibiting the CRM1 binding to the TERT NES-like motif.
Seimiya
H
H
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan. seimiya@saturn.med.nyu.edu
Sawada
H
H
Muramatsu
Y
Y
Shimizu
M
M
Ohko
K
K
Yamane
K
K
Tsuruo
T
T
D048948:14-3-3 Proteins; D000595:Amino Acid Sequence; D001483:Base Sequence; D001692:Biological Transport; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005799:Genes, Dominant; D006801:Humans; D028884:Karyopherins; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase; D000097606:Exportin 1 Protein
D048948:14-3-3 Proteins; D002352:Carrier Proteins; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D010446:Peptide Fragments; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D019098:Telomerase; D014446:Tyrosine 3-Monooxygenase; D000097606:Exportin 1 Protein; C038753:leptomycin B