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The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons
M H Lee1, M Nikolic, C A Baptista
1Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Abstract:
Cell cycle withdrawal in postmitotic cells involves cyclin-dependent kinase (Cdk) inhibitors that repress cell cycle Cdk activity. During mouse neurogenesis, cortical postmitotic neurons are shown here to accumulate high levels of the p27 Cdk inhibitor compared with their progenitor neuroblasts. Elevated p27 levels in staged embryo brain extracts correlate with p27 binding to Cdk2, and Cdk inactivation. Yet, Cdk5, which is associated with the noncyclin activator p35 in neurons, remains active in the presence of high p27 levels. Both in vitro and in vivo, p27 and related inhibitors can recognize a cyclin D-Cdk5 complex but not a p35-Cdk5 complex. The results indicate that the choice of activator determines the susceptibility of Cdk5 to p27 and related Cdk inhibitors, and thus its ability to act in postmitotic cells.
Insights
Postmitotic neurons use p27 cyclin-dependent kinase (Cdk) inhibitors to halt cell division. Cdk5
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Cell cycle withdrawal is crucial for neuronal differentiation.
- Cyclin-dependent kinase (Cdk) inhibitors regulate cell cycle progression.
- Postmitotic neurons must exit the cell cycle to differentiate.
Purpose of the Study:
- To investigate the role of Cdk inhibitors, specifically p27, in cell cycle withdrawal of postmitotic neurons.
- To determine how Cdk5 activity is regulated in postmitotic neurons despite high p27 levels.
Main Methods:
- Analysis of p27 Cdk inhibitor levels in mouse embryo brain extracts.
- Biochemical assays to assess p27 binding to Cdk2 and Cdk5.
- In vitro and in vivo experiments to study the interaction of p27 with different Cdk5 activator complexes.
Main Results:
- Postmitotic neurons accumulate high levels of the p27 Cdk inhibitor compared to progenitor neuroblasts.
- Elevated p27 levels correlate with Cdk2 inactivation but not Cdk5 inactivation.
- p27 and related inhibitors bind to cyclin D-Cdk5 complexes but not p35-Cdk5 complexes.
Conclusions:
- The choice of Cdk activator dictates Cdk5 susceptibility to inhibitors like p27.
- This differential regulation allows Cdk5 to remain active in postmitotic neurons, facilitating their function.
- p27 plays a key role in cell cycle exit during neurogenesis by selectively inhibiting specific Cdk complexes.