Involvement of cyclin D1/CDK4 and pRb mediated by PI3K/AKT pathway activation in Pb2+ -induced neuronal death in cultured hippocampal neurons.
Lead (Pb) is widely recognized as a neurotoxicant. One of the suggested mechanisms of lead neurotoxicity is apoptotic cell death. And the mechanism by which Pb(2+) causes neuronal death is not well understood. The present study sought to examine the obligate nature of cyclin D1/cyclin-dependent kinase 4 (CDK4), phosphorylation of its substrate retinoblastoma protein (pRb) and its select upstream signal phosphoinositide 3-kinase (PI3K)/AKT pathway in the death of primary cultured rat hippocampal neurons evoked by Pb(2+). Our data showed that lead treatment of primary hippocampal cultures results in dose-dependent cell death. Inhibition of CDK4 prevented Pb(2+)-induced neuronal death significantly but was incomplete. In addition, we demonstrated that the levels of cyclin D1 and pRb/p107 were increased during Pb(2+) treatment. These elevated expression persisted up to 48 h, returning to control levels after 72 h. We also presented pharmacological and morphological evidences that cyclin D1/CDK4 and pRb/p107 were required for such kind of neuronal death. Addition of the PI3K inhibitor LY294002 (30 microM) or wortmannin (100 nM) significantly rescued the cultured hippocampal neurons from death caused by Pb(2+). And that Pb(2+)-elicited phospho-AKT (Ser473) participated in the induction of cyclin D1 and partial pRb/p107 expression. These results provide evidences that cell cycle elements play a required role in the death of neurons evoked by Pb(2+) and suggest that certain signaling elements upstream of cyclin D1/CDK4 are modified and/or required for this form of neuronal death.
Li
Chenchen
C
Department of Neurobiology and Biophysics, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, PR China. glacier@mail.ustc.edu.cn
Xing
Tairan
T
Tang
Mingliang
M
Yong
Wu
W
Yan
Dan
D
Deng
Hongmin
H
Wang
Huili
H
Wang
Ming
M
Chen
Jutao
J
Ruan
Diyun
D
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007854:Lead / Q000008:administration & dosage / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D019938:Cyclin D1; D007854:Lead; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051358:Cyclin-Dependent Kinase 4