Ubiquitin/proteasome-mediated degradation of p19INK4d determines its periodic expression during the cell cycle.
Assembly and activity of the proto-oncogenic cyclin D/CDK4(6) complexes, the major driving force of G1 phase progression, is negatively regulated by a family of INK4 CDK inhibitors p16INK4a, p15INK4b, p18INK4c, and p19INK4d. Expression of the INK4 family members is controlled at the transcriptional level, through differential response to environmental and intracellular signals such as cytokines, oncogenic overload, or cellular senescence. Here we show that the periodic oscillation of the p19INK4d protein during the cell cycle is determined by the ubiquitin/proteasome-dependent mechanism, allowing the protein abundance to follow the changes in its mRNA expression. Within the INK4 family, this regulatory mode appears restricted to p19INK4d whose ubiquitination was dependent on the integrity of lysine 62, and binding to CDK4. These results highlight unexpected differences among the INK4 inhibitors, and suggest how p19INK4d may help regulate the rate of cyclin D/CDK4(6) complex formation, and thereby timely progression through the mammalian cell division cycle. Oncogene (2000) 19, 2870 - 2876
Thullberg
M
M
Danish Cancer Society, Institute of Cancer Biology, Strandboulevarden 49, DK-2100 Copenhagen O, Denmark.
Bartek
J
J
Lukas
J
J
D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins; D014452:Ubiquitins / Q000502:physiology*
C493974:CDKN2D protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D014452:Ubiquitins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex