Mechanisms of telomerase induction during vascular smooth muscle cell proliferation.
Telomeres are primarily controlled by a highly specialized DNA polymerase termed telomerase. Recent studies have demonstrated that introduction of the telomerase catalytic component (TERT) into telomerase-negative cells activates telomerase and extends cell life span, whereas mice lacking telomerase activity revealed impaired cell proliferation in some organs as well as reduced tumorigenesis. These reports suggest that telomerase plays an important role in long-term cell viability and cell proliferation. However, the mechanism or mechanisms by which telomerase is induced or regulated remains to be elucidated. We report here that primary vascular smooth muscle cells (VSMCs) express telomerase and that increased telomerase activity correlates with cell proliferation. Inhibition of telomerase diminished growth of VSMCs, which suggests a crucial role for telomerase activation in the regulation of VSMC proliferation. We propose a novel model whereby telomerase is first activated in the cytoplasm before cell proliferation, followed by accumulation of activity in the nucleus during the logarithmic phase of cell growth. Activation of telomerase in VSMCs was linked to phosphorylation of TERT. The protein kinase inhibitor H7 suppressed the activation of telomerase in the cytoplasm and also inhibited the accumulation of TERT as well as telomerase activity in the nucleus. These data suggest that posttranslational modification of TERT by phosphorylation is important for activation and accumulation of telomerase into the nucleus in the process of VSMC proliferation.
Minamino
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Department of Medicine, Division of Newborn Medicine, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Kourembanas
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D028044:Phosphate-Binding Proteins; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D028044:Phosphate-Binding Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C498416:Tep1 protein, rat; C422952:telomerase RNA; D012313:RNA; D000255:Adenosine Triphosphate; D019098:Telomerase