Related Experiment Videos
p21(Cip1) Promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export
Jodi R Alt1, Andrew B Gladden, J Alan Diehl
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Abstract:
There is increasing evidence that p21(Cip1) and p27(Kip1) are requisite positive regulators of cyclin D1.CDK4 assembly and nuclear accumulation. Both Cip and Kip proteins can promote nuclear accumulation of cyclin D1, but the underlying mechanism has not been elucidated. We now provide evidence that p21(Cip1) promotes the nuclear accumulation of cyclin D1 complexes via inhibition of cyclin D1 nuclear export. In vivo, we demonstrate that p21(Cip1) can inhibit glycogen synthase kinase 3 beta-triggered cyclin D1 nuclear export and phosphorylation-dependent nucleocytoplasmic shuttling. Furthermore, we find that cyclin D1 nuclear accumulation in p21/p27 null cells can be restored through inhibition of CRM1-dependent nuclear export. The ability of p21(Cip1) to inhibit cyclin D1 nuclear export correlates with its ability to bind to Thr-286-phosphorylated cyclin D1 and thereby prevents cyclin D1.CRM1 association.
Insights
The p21 protein (cyclin-dependent kinase inhibitor 1) prevents cyclin D1 from exiting the cell nucleus. This mechanism is crucial for cyclin D1-CDK4 complex assembly and function.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- p21(Cip1) and p27(Kip1) are known regulators of cyclin D1.CDK4 complex formation.
- The precise mechanism by which these proteins promote cyclin D1 nuclear accumulation is not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which p21(Cip1) facilitates cyclin D1 nuclear accumulation.
- To investigate the role of p21(Cip1) in regulating cyclin D1 nuclear export.
Main Methods:
- In vivo studies examining cyclin D1 nuclear export and nucleocytoplasmic shuttling.
- Experiments involving p21/p27 null cells and inhibition of CRM1-dependent nuclear export.
- Analysis of p21(Cip1) binding to phosphorylated cyclin D1 and its association with CRM1.
Main Results:
- p21(Cip1) inhibits cyclin D1 nuclear export, thereby promoting its nuclear accumulation.
- p21(Cip1) prevents glycogen synthase kinase 3 beta-triggered cyclin D1 nuclear export and phosphorylation-dependent shuttling.
- Restoration of cyclin D1 nuclear accumulation in p21/p27 null cells was achieved by inhibiting CRM1-dependent nuclear export.
- p21(Cip1) binds to Thr-286-phosphorylated cyclin D1, preventing its association with CRM1.
Conclusions:
- p21(Cip1) acts as a positive regulator of cyclin D1 nuclear accumulation by inhibiting its nuclear export.
- The binding of p21(Cip1) to phosphorylated cyclin D1 is key to preventing CRM1-mediated nuclear export.