PMID- 10611320
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 26
DP  - 1999 Dec 21
TI  - Transforming growth factor beta targeted inactivation of cyclin
      E:cyclin-dependent kinase 2 (Cdk2) complexes by inhibition of Cdk2 activating
      kinase activity.
PG  - 14961-6
AB  - Transforming growth factor beta (TGF-beta)-mediated G(1) arrest previously has
      been shown to specifically target inactivation of cyclin D:cyclin-dependent
      kinase (Cdk) 4/6 complexes. We report here that TGF-beta-treated human HepG2
      hepatocellular carcinoma cells arrest in G(1), but retain continued cyclin
      D:Cdk4/6 activity and active, hypophosphorylated retinoblastoma tumor suppressor 
      protein. Consistent with this observation, TGF-beta-treated cells failed to
      induce p15(INK4b), down-regulate CDC25A, or increase levels of p21(CIP1),
      p27(KIP1), and p57(KIP2). However, TGF-beta treatment resulted in the specific
      inactivation of cyclin E:Cdk2 complexes caused by absence of the activating
      Thr(160) phosphorylation on Cdk2. Whole-cell lysates from TGF-beta-treated cells 
      showed inhibition of Cdk2 Thr(160) Cdk activating kinase (CAK) activity; however,
      cyclin H:Cdk7 activity, a previously assumed mammalian CAK, was not altered.
      Saccharomyces cerevisiae contains a genetically and biochemically proven CAK
      gene, CAK1, that encodes a monomeric 44-kDa Cak1p protein unrelated to Cdk7.
      Anti-Cak1p antibodies cross-reacted with a 45-kDa human protein with CAK activity
      that was specifically down-regulated in response to TGF-beta treatment. Taken
      together, these observations demonstrate that TGF-beta signaling mediates a G(1) 
      arrest in HepG2 cells by targeting Cdk2 CAK and suggests the presence of at least
      two mammalian CAKs: one specific for Cdk2 and one for Cdk4/6.
FAU - Nagahara, H
AU  - Nagahara H
AD  - Howard Hughes Medical Institute, Department of Pathology, Washington University
      School of Medicine, St. Louis, MO 63110, USA.
FAU - Ezhevsky, S A
AU  - Ezhevsky SA
FAU - Vocero-Akbani, A M
AU  - Vocero-Akbani AM
FAU - Kaldis, P
AU  - Kaldis P
FAU - Solomon, M J
AU  - Solomon MJ
FAU - Dowdy, S F
AU  - Dowdy SF
LA  - eng
GR  - R01 GM047830/GM/NIGMS NIH HHS/United States
GR  - GM47830/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (CCNH protein, human)
RN  - 0 (Cyclin E)
RN  - 0 (Cyclin H)
RN  - 0 (Cyclins)
RN  - 0 (Transforming Growth Factor beta)
RN  - 2ZD004190S (Threonine)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (CDC2-CDC28 Kinases)
RN  - EC 2.7.11.22 (CDK2 protein, human)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 2.7.11.22 (cyclin-dependent kinase-activating kinase)
SB  - IM
MH  - *CDC2-CDC28 Kinases
MH  - Cyclin E/*metabolism
MH  - Cyclin H
MH  - Cyclin-Dependent Kinase 2
MH  - Cyclin-Dependent Kinases/antagonists & inhibitors/*metabolism
MH  - Cyclins/metabolism
MH  - Down-Regulation
MH  - Enzyme Activation
MH  - G1 Phase/*drug effects
MH  - Humans
MH  - Models, Biological
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/*metabolism
MH  - Threonine/metabolism
MH  - Transforming Growth Factor beta/*pharmacology
MH  - Tumor Cells, Cultured
PMC - PMC24755
EDAT- 1999/12/28 00:00
MHDA- 1999/12/28 00:01
CRDT- 1999/12/28 00:00
PHST- 1999/12/28 00:00 [pubmed]
PHST- 1999/12/28 00:01 [medline]
PHST- 1999/12/28 00:00 [entrez]
AID - 10.1073/pnas.96.26.14961 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14961-6. doi:
      10.1073/pnas.96.26.14961.