PMID- 10542199
OWN - NLM
STAT- MEDLINE
DCOM- 19991213
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 45
DP  - 1999 Nov 5
TI  - Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger
      apoptosis through the phosphorylation of retinoblastoma protein in FaO hepatoma
      cells.
PG  - 31775-83
AB  - 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.
FAU - Choi, K S
AU  - Choi KS
AD  - Laboratory of Endocrinology, Institute for Medical Sciences, Ajou University
      School of Medicine, 5 Wonchon-Dong, Paldal-Gu, Suwon 442-749, Korea.
      kschoi@madang.ajou.ac.kr
FAU - Eom, Y W
AU  - Eom YW
FAU - Kang, Y
AU  - Kang Y
FAU - Ha, M J
AU  - Ha MJ
FAU - Rhee, H
AU  - Rhee H
FAU - Yoon, J W
AU  - Yoon JW
FAU - Kim, S J
AU  - Kim SJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Purines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Retinoblastoma Protein)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0ES1C2KQ94 (Roscovitine)
RN  - 6A839B2HYS (olomoucine)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (CDC2 Protein Kinase)
RN  - EC 2.7.11.22 (CDC2-CDC28 Kinases)
RN  - EC 2.7.11.22 (Cdk2 protein, rat)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - P39Y9652YJ (Kinetin)
SB  - IM
MH  - Animals
MH  - *Apoptosis/drug effects
MH  - CDC2 Protein Kinase/*metabolism
MH  - *CDC2-CDC28 Kinases
MH  - Cell Cycle
MH  - Cell Death
MH  - Cyclin-Dependent Kinase 2
MH  - Cyclin-Dependent Kinases/*metabolism
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Kinetin
MH  - Liver Neoplasms, Experimental/*metabolism
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Purines/pharmacology
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Retinoblastoma Protein/*metabolism
MH  - Roscovitine
MH  - Transforming Growth Factor beta/*pharmacology
MH  - Tumor Cells, Cultured
EDAT- 1999/11/05 00:00
MHDA- 1999/11/05 00:01
CRDT- 1999/11/05 00:00
PHST- 1999/11/05 00:00 [pubmed]
PHST- 1999/11/05 00:01 [medline]
PHST- 1999/11/05 00:00 [entrez]
AID - 10.1074/jbc.274.45.31775 [doi]
AID - S0021-9258(19)51487-9 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Nov 5;274(45):31775-83. doi: 10.1074/jbc.274.45.31775.