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Translational control of p27Kip1 accumulation during the cell cycle
1Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
Cell cycle phase transitions in eukaryotic cells are driven by regulation of the activity of protein kinases known as cyclin-dependent kinases (Cdks). A broad spectrum of Cdk-inhibitory activity associated with a 28-kilodalton protein (p28lck1) was induced in cells treated with the drug lovastatin or upon density-mediated growth arrest and was periodic in the cell cycle, with peak activity in G1. The p28lck1 protein was shown to be identical to p27Kip1, and the periodic or induced inhibitory activity resulted from a periodic accumulation of the protein. Variations in the amount of p27 protein occurred, whereas the abundance of the p27 messenger RNA remained unchanged. In every instance investigated, the posttranscriptional alteration of p27 protein levels was achieved in part by a mechanism of translational control, although in density-arrested fibroblasts and thymidine-arrested HeLa cells the half-life of the protein was also changed.
Insights
Cell cycle regulation involves cyclin-dependent kinases (Cdks). A protein, p27Kip1, shows periodic cell cycle activity, primarily controlled by its accumulation rather than mRNA levels.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Cell cycle progression in eukaryotes is tightly regulated by cyclin-dependent kinases (Cdks).
- Dysregulation of cell cycle control is a hallmark of many diseases, including cancer.
Purpose of the Study:
- To investigate the molecular mechanisms underlying cell cycle arrest induced by lovastatin and density-mediated growth arrest.
- To identify and characterize the protein responsible for Cdk-inhibitory activity observed during these conditions.
Main Methods:
- Induction of Cdk-inhibitory activity in cells treated with lovastatin or subjected to density-mediated growth arrest.
- Protein identification and characterization, including molecular weight determination (p28lck1).
- Analysis of p27Kip1 protein and messenger RNA (mRNA) levels during cell cycle progression and arrest.
Main Results:
- A 28-kilodalton protein (p28lck1) exhibiting broad Cdk-inhibitory activity was identified.
- p28lck1 was found to be identical to the known cell cycle inhibitor p27Kip1.
- The inhibitory activity correlated with periodic accumulation of p27Kip1 protein, independent of mRNA level changes, indicating post-transcriptional regulation, including translational control and altered protein half-life.
Conclusions:
- Cell cycle arrest and periodic activity are regulated by post-transcriptional control of p27Kip1 protein levels.
- Translational control and protein degradation are key mechanisms modulating p27Kip1 levels, impacting Cdk activity and cell cycle progression.