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Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger apoptosis through the phosphorylation of retinoblastoma protein in FaO hepatoma cells.

Choi, KS; Eom, YW; Kang, Y; Ha, MJ; Rhee, H; Yoon, JW; Kim, SJ
The Journal of biological chemistry, 274(45):31775-31783, 1999
Journal Title
The Journal of biological chemistry
The signaling pathway leading to TGF-beta1-induced apoptosis was investigated using a TGF-beta1-sensitive hepatoma cell line, FaO. Cell cycle analysis demonstrated that the accumulation of apoptotic cells was preceded by a progressive decrease of the cell population in the G(1) phase concomitant with a slight increase of the cell population in the G(2)/M phase in response to TGF-beta1. TGF-beta1 induced a transient increase in the expression of Cdc2, cyclin A, cyclin B, and cyclin D1 at an early phase of apoptosis. During TGF-beta1-induced apoptosis, the transient increase in cyclin-dependent kinase (Cdk) activities coincides with a dramatic increase in the hyperphosphorylated forms of RB. Treatment with roscovitine or olomoucine, inhibitors of Cdc2 and Cdk2, blocked TGF-beta1-induced apoptosis by inhibiting RB phosphorylation. Overexpression of Bcl-2 or adenovirus E1B 19K suppressed TGF-beta1-induced apoptosis by blocking the induction of Cdc2 mRNA and the subsequent activation of Cdc2 kinase, whereas activation of Cdk2 was not affected, suggesting that Cdc2 plays a more critical role in TGF-beta1-induced apoptosis. In conclusion, we present the evidence that Cdc2 and Cdk2 kinase activity transiently induced by TGF-beta1 phosphorylates RB as a physiological target in FaO cells and that RB hyperphosphorylation may trigger abrupt cell cycle progression, leading to irreversible cell death.
MeSH terms
AnimalsApoptosis*/drug effectsCDC2 Protein Kinase/metabolism*CDC2-CDC28 Kinases*Cell CycleCell DeathCyclin-Dependent Kinase 2Cyclin-Dependent Kinases/metabolism*Enzyme ActivationEnzyme Inhibitors/pharmacologyKinetinLiver Neoplasms, Experimental/metabolism*PhosphorylationProtein-Serine-Threonine Kinases/metabolism*Proto-Oncogene Proteins c-bcl-2/metabolismPurines/pharmacologyRNA, Messenger/metabolismRatsRetinoblastoma Protein/metabolism*Transforming Growth Factor beta/pharmacology*Tumor Cells, Cultured
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
Journal Papers > School of Medicine / Graduate School of Medicine > Endocrinology & Metabolism
AJOU Authors
최, 경숙강, 엽윤, 지원
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