title: Role of cell cycle-associated proteins in microglial proliferation in the axotomized rat facial nucleus.
abstract: We analyzed cell cycle-associated proteins, including cyclins, cyclin-dependent protein kinases (Cdks), and Cdk inhibitors (CdkIs) in the axotomized rat facial nucleus. Immunoblotting revealed that cyclin A and cyclin D are induced 3-5 days after transection. The induced cyclin A was immunohistochemically recognized in microglia. Cdk2 and Cdk4 were also detected in the facial nucleus. The CdkI p21 was elevated 5 days after axotomy. Inhibition experiments in vitro using a cFms (receptor for macrophage-colony stimulating factor, M-CSF) inhibitor indicated that M-CSF-cFms signaling leads to upregulation of the levels of cyclin A, cyclin D, proliferating cell nuclear antigen (PCNA), and cFms in microglia. The role of cyclin A/Cdk2 activity in M-CSF-dependent microglial proliferation was ascertained using the specific inhibitor purvalanol A. Experiments using specific mitogen-activated protein kinase inhibitors suggested that c-Jun N-terminal kinase (JNK) is associated with M-CSF-dependent induction of cyclins and PCNA, whereas p38 is associated with cFms induction. Both JNK and p38 were proved to be phosphorylated by stimulation with M-CSF. Our results indicated that cyclin A, cyclin D, Cdk2, Cdk4, and p21 are involved in microglial proliferation in the transected facial nucleus, and that the M-CSF-dependent upregulations of cyclins/PCNA and cFms in microglia are differentially regulated by JNK and p38.
authors.affiliation: Department of Bioinformatics, Faculty of Engineering, Soka University, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kohsaka
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D019771:Axotomy / Q000009:adverse effects; D001933:Brain Stem / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020220:Facial Nerve Injuries / Q000209:etiology / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein; D066298:In Vitro Techniques; D016215:Macrophage-Activating Factors / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D039481:CD11b Antigen; D018797:Cell Cycle Proteins; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D016215:Macrophage-Activating Factors; D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D020928:Mitogen-Activated Protein Kinases