Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1-S transition.
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.
Song
M S
MS
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Song
S J
SJ
Kim
S J
SJ
Nakayama
K
K
Nakayama
K I
KI
Lim
D-S
DS
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000235:genetics; D016196:S Phase / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D054875:Ubiquitination / Q000235:genetics
D056741:Cyclin D; D016213:Cyclins; C411762:RASSF1 protein, human; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D051358:Cyclin-Dependent Kinase 4; D046988:Proteasome Endopeptidase Complex