Role of cyclin D1 cytoplasmic sequestration in the survival of postmitotic neurons.
Cyclin D-dependent kinases phosphorylate the retinoblastoma (Rb) protein and play a critical role in neuronal cell cycle control and apoptosis. Here we show that cyclin D1 became predominantly cytoplasmic as primary cortical progenitor cells underwent cell cycle withdrawal and terminal differentiation. Furthermore, ectopically expressed cyclin D1 sequestered in the cytoplasm of postmitotic neurons, whereas it efficiently entered the nucleus of proliferating progenitor cells. Cytoplasmic cyclin D1 were complexed with cyclin-dependent kinase 4 (CDK4), and also with CDK inhibitors, p27(Kip)(I) or p21(Cip)(I), which positively regulate assembly and nuclear accumulation of the cyclin D1-CDK4 complex. Although overexpression of p21(Cip)(I) promoted cyclin D1 nuclear localization, inhibition of either glycogen synthase kinase 3beta- or CRM1-mediated cyclin D1 nuclear export did not, suggesting that the inhibition of its nuclear import, rather than the acceleration of nuclear export, contributes to cytoplasmic sequestration of cyclin D1 in postmitotic neurons. In differentiated progenitor cells, nuclear localization of ectopic cyclin D1 induced apoptosis, and the DNA-damaging compound camptothecin caused nuclear accumulation of endogenous cyclin D1, accompanied by Rb phosphorylation. These results indicate that nuclear accumulation of cyclin D1 is inhibited in postmitotic neurons and suggest a role of its subcellular localization in neuronal death and survival.
Sumrejkanchanakij
Piyamas
P
Section of Molecular Embryology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
Tamamori-Adachi
Mimi
M
Matsunaga
Yuko
Y
Eto
Kazuhiro
K
Ikeda
Masa-Aki
MA
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002540:Cerebral Cortex / Q000166:cytology*; D019938:Cyclin D1 / Q000502:physiology*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011518:Proto-Oncogene Proteins
D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases