PMID- 18071316
OWN - NLM
STAT- MEDLINE
DCOM- 20080603
LR  - 20091119
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 27
IP  - 22
DP  - 2008 May 15
TI  - Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via 
      ubiquitin-mediated degradation at the G1-S transition.
PG  - 3176-85
AB  - The tumor suppressor RASSF1A is inactivated in many human cancers and is 
      implicated in regulation of microtubule stability, cell cycle progression and 
      apoptosis. However, the precise mechanisms of RASSF1A action and their regulation 
      remain unclear. Here we show that Skp2, an oncogenic subunit of the 
      Skp1-Cul1-F-box ubiquitin ligase complex, interacts with, ubiquitinates, and 
      promotes the degradation of RASSF1A at the G1-S transition of the cell cycle. 
      This Skp2-dependent destruction of RASSF1A requires phosphorylation of the latter 
      on serine-203 by cyclin D-cyclin-dependent kinase 4. Interestingly, mutation of 
      RASSF1A-phosphorylation site Ser(203) to alanine results in a delay in cell cycle 
      progression from G1 to S phase. Moreover, enforced expression of Skp2 abolishes 
      the inhibitory effect of RASSF1A on cell proliferation. Finally, the delay in 
      G1-S progression after Skp2 removal is normalized by depletion of RASSF1A. These 
      findings suggest that the Skp2-mediated degradation of RASSF1A plays an important 
      role in cell proliferation and survival.
FAU - Song, M S
AU  - Song MS
AD  - Department of Biological Sciences, Korea Advanced Institute of Science and 
      Technology, Daejeon, Korea.
FAU - Song, S J
AU  - Song SJ
FAU - Kim, S J
AU  - Kim SJ
FAU - Nakayama, K
AU  - Nakayama K
FAU - Nakayama, K I
AU  - Nakayama KI
FAU - Lim, D-S
AU  - Lim DS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071210
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Cyclin D)
RN  - 0 (Cyclins)
RN  - 0 (RASSF1 protein, human)
RN  - 0 (S-Phase Kinase-Associated Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Animals
MH  - *Cell Proliferation
MH  - Cell Survival/genetics
MH  - Cells, Cultured
MH  - Cyclin D
MH  - Cyclin-Dependent Kinase 4/metabolism
MH  - Cyclins/metabolism
MH  - *G1 Phase/genetics
MH  - Genes, Tumor Suppressor/physiology
MH  - HeLa Cells
MH  - Humans
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Phosphorylation
MH  - Proteasome Endopeptidase Complex/*metabolism
MH  - Protein Binding
MH  - Protein Processing, Post-Translational/genetics
MH  - *S Phase/genetics
MH  - S-Phase Kinase-Associated Proteins/metabolism/*physiology
MH  - Transfection
MH  - Tumor Suppressor Proteins/genetics/*metabolism/physiology
MH  - *Ubiquitination/genetics
EDAT- 2007/12/12 09:00
MHDA- 2008/06/05 09:00
CRDT- 2007/12/12 09:00
PHST- 2007/12/12 09:00 [pubmed]
PHST- 2008/06/05 09:00 [medline]
PHST- 2007/12/12 09:00 [entrez]
AID - 1210971 [pii]
AID - 10.1038/sj.onc.1210971 [doi]
PST - ppublish
SO  - Oncogene. 2008 May 15;27(22):3176-85. doi: 10.1038/sj.onc.1210971. Epub 2007 Dec 
      10.