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Ubiquitin/proteasome-mediated degradation of p19INK4d determines its periodic expression during the cell cycle
M Thullberg1, J Bartek, J Lukas
1Danish Cancer Society, Institute of Cancer Biology, Strandboulevarden 49, DK-2100 Copenhagen O, Denmark.
Abstract:
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
Insights
The cell cycle regulator p19INK4d protein levels oscillate due to ubiquitin/proteasome degradation, unlike other INK4 inhibitors. This mechanism allows p19INK4d to control cyclin D/CDK4(6) complex formation and cell cycle progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cyclin D/CDK4(6) complexes drive G1 phase progression and are regulated by INK4 inhibitors.
- INK4 family gene expression is controlled transcriptionally by various signals.
Purpose of the Study:
- To investigate the post-transcriptional regulation of p19INK4d protein levels during the cell cycle.
- To understand the mechanism controlling p19INK4d protein abundance and its relation to mRNA expression.
Main Methods:
- Studied the ubiquitin/proteasome-dependent mechanism regulating p19INK4d protein oscillation.
- Investigated p19INK4d ubiquitination, focusing on lysine 62 and CDK4 binding.
Main Results:
- p19INK4d protein levels oscillate periodically during the cell cycle via ubiquitin/proteasome degradation.
- This degradation mechanism allows p19INK4d protein abundance to mirror mRNA expression changes.
- p19INK4d ubiquitination depends on lysine 62 integrity and CDK4 binding, a unique feature within the INK4 family.
Conclusions:
- p19INK4d exhibits unique post-transcriptional regulation compared to other INK4 inhibitors.
- This mechanism suggests p19INK4d plays a specific role in regulating cyclin D/CDK4(6) complex formation and cell division timing.