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J Biol Chem, Vol. 274, Issue 45, 31775-31783, November 5, 1999
From the The signaling pathway leading to TGF-
Cdc2 and Cdk2 Kinase Activated by Transforming Growth Factor-
1
Trigger Apoptosis through the Phosphorylation of Retinoblastoma Protein
in FaO Hepatoma Cells
,,,
,**, and
Laboratory of Endocrinology and
¶ Laboratory of Medical Genetics, Institute for Medical Sciences,
Ajou University School of Medicine, 5 Wonchon-Dong, Paldal-Gu, Suwon
442-749, Korea, the Laboratory of Cell Regulation and
Carcinogenesis, National Cancer Institute, Bethesda, Maryland
20892-5055, and the ** Laboratory of Viral and Immunopathogenesis of
Diabetes, Department of Microbiology and Infectious Diseases, Julia
McFarlance Diabetes Research Centre, Faculty of Medicine, the
University of Calgary, Alberta T2N 4N1, Canada4
1-induced
apoptosis was investigated using a TGF-1-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 G1 phase concomitant with a slight
increase of the cell population in the G2/M phase in
response to TGF-1. TGF-1 induced a transient increase in the
expression of Cdc2, cyclin A, cyclin B, and cyclin D1 at an early phase
of apoptosis. During TGF-1-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-1-induced apoptosis by inhibiting RB phosphorylation.
Overexpression of Bcl-2 or adenovirus E1B 19K suppressed
TGF-1-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-1-induced apoptosis. In conclusion, we present the evidence
that Cdc2 and Cdk2 kinase activity transiently induced by TGF-1
phosphorylates RB as a physiological target in FaO cells and that RB
hyperphosphorylation may trigger abrupt cell cycle progression,
leading to irreversible cell death.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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