Nuclear factor-kappaB-dependent cyclin D1 induction and DNA replication associated with N-methyl-D-aspartate receptor-mediated apoptosis in rat striatum.
Cell cycle reentry has been found during apoptosis of postmitotic neurons under certain pathological conditions. To evaluate whether nuclear factor-kappaB (NF-kappaB) activation promotes cell cycle entry and neuronal apoptosis, we studied the relation among NF-kappaB-mediated cyclin induction, bromodeoxyuridine (BrdU) incorporation, and apoptosis initiation in rat striatal neurons following excitotoxic insult. Intrastriatally injected N-methyl-D-aspartate receptor agonist quinolinic acid (QA, 60 nmol) elicited a rise in cyclin D1 mRNA and protein levels (P<0.05). QA-induced NF-kappaB activation occurred in striatal neurons and nonneuronal cells and partially colocalized with elevated cyclin D1 immunoreactivity and TUNEL-positive nuclei. QA triggered DNA replication as evidenced by BrdU incorporation; some striatal BrdU-positive cells were identified as neurons by colocalization with NeuN. Blockade of NF-kappaB nuclear translocation with the recombinant peptide NF-kappaB SN50 attenuated the QA-induced elevation in cyclin D1 and BrdU incorporation. QA-induced internucleosomal DNA fragmentation was blunted by G(1)/S-phase cell cycle inhibitors. These findings suggest that NF-kappaB activation stimulates cyclin D1 expression and triggers DNA replication in striatal neurons. Excitotoxin-induced neuronal apoptosis may thus result from, at least partially, a failed cell cycle attempt.
Liang
Zhong-Qin
ZQ
Department of Pharmacology, Soochow University School of Medicine, Suzhou, China.
Wang
Xiaoxia
X
Li
Ling-Yun
LY
Wang
Yumei
Y
Chen
Ren-Wu
RW
Chuang
De-Maw
DM
Chase
Thomas N
TN
Qin
Zheng-Hong
ZH
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology*; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007839:Functional Laterality; D020287:In Situ Nick-End Labeling / Q000379:methods; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C118258:SN50 peptide; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D010751:Phosphopyruvate Hydratase; D017378:Quinolinic Acid; D001973:Bromodeoxyuridine