Geldanamycin induces G2 arrest in U87MG glioblastoma cells through downregulation of Cdc2 and cyclin B1.
Cell cycle progression requires precise expression and activation of several cyclins and cyclin-dependent kinases. Geldanamycin (GA) affects cell cycle progression in various kinds of cells. We analyzed GA-induced cell cycle regulation in glioblastoma cells. GA-induced G2 or M arrest in glioblastoma cells in a cell line-dependent manner. GA decreased the expression of Cdc2 and cyclin B1 in U87MG cells. And phosphorylated Cdc2 decreased along with Cdc2 in the GA-treated cells. This cell line showed G2 arrest after GA treatment. In contrast, GA failed to down-regulate these cell cycle regulators in U251MG cells. In U251MG cells, the cell cycle was arrested at M phase in addition to G2 by GA. Next, we analyzed the mechanism of the GA-induced regulation of Cdc2 and cyclin B1 in U87MG cells. Cdc2 and cyclin B1 were ubiquitinated by GA. MG132 abrogated the GA-induced decrease of Cdc2 and cyclin B1 indicating that these proteins were degraded by proteasomes. In conclusion, GA controls the stability of Cdc2 and cyclin B1 in glioblastomas cell species-dependently. Cdc2 and cyclin B1 might be responsible for the different responses of glioblastoma cell lines to GA.
Nomura
Naoko
N
Department of Ophthalmology, Kanazawa Social Insurance Hospital, Kanazawa, Japan. nomura413jp@yahoo.co.jp
Nomura
Motohiro
M
Newcomb
Elizabeth W
EW
Zagzag
David
D
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism*; D056744:Cyclin B1; D015536:Down-Regulation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects* / Q000502:physiology; D005909:Glioblastoma / Q000473:pathology*; D006207:Half-Life; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D047029:Lactams, Macrocyclic; D025801:Ubiquitin; D016203:CDC2 Protein Kinase; D046988:Proteasome Endopeptidase Complex; C001277:geldanamycin