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Published on: March 21, 2022
A pathway in quiescent cells that controls p27Kip1 stability, subcellular localization, and tumor suppression
Arnaud Besson1, Mark Gurian-West, Xueyan Chen
1Howard Hughes Medical Institute, Division of Basic Sciences, Seattle, Washington 98109, USA.
Abstract:
We have created two knock-in mouse models to study the mechanisms that regulate p27 in normal cells and cause misregulation of p27 in tumors: p27(S10A), in which Ser10 is mutated to Ala; and p27(CK-), in which point mutations abrogate the ability of p27 to bind cyclins and CDKs. These two mutant alleles identify steps in a pathway that controls the proteasomal degradation of p27 uniquely in quiescent cells: Dephosphorylation of p27 on Ser10 inhibits p27 nuclear export and promotes its assembly into cyclin-CDK complexes, which is, in turn, necessary for p27 turnover. We further show that Ras-dependent lung tumorigenesis is associated with increased phosphorylation on Ser10 and cytoplasmic mislocalization of p27. Indeed, we find that p27(S10A) is refractory to Ras-induced cytoplasmic translocation and that p27(S10A) mice are tumor resistant. Thus, phosphorylation of p27 on Ser10 is an important event in the regulation of the tumor suppressor function of p27.
Insights
Researchers developed two mouse models to investigate p27 regulation. They discovered that p27 phosphorylation on Ser10 is crucial for tumor suppressor function and preventing tumor development.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- The cell cycle inhibitor p27 (also known as CDKN1B) plays a critical role in regulating cell proliferation and is often misregulated in various cancers.
- Understanding the precise mechanisms controlling p27 stability and localization is essential for developing targeted cancer therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms governing p27 proteasomal degradation in normal quiescent cells.
- To investigate the role of p27 misregulation in Ras-driven lung tumorigenesis.
- To determine the functional significance of p27 phosphorylation at Serine 10 (S10) in tumor suppression.
Main Methods:
- Generation of two knock-in mouse models: p27(S10A) with Ser10 mutated to Alanine, and p27(CK-) with mutations disrupting cyclin-CDK binding.
- Analysis of p27 degradation pathways in quiescent cells.
- Investigation of p27 phosphorylation and localization in the context of Ras-induced lung tumors.
- Assessment of tumor development and resistance in p27 mutant mice.
Main Results:
- Identified a pathway controlling p27 proteasomal degradation in quiescent cells, involving dephosphorylation at S10, inhibition of nuclear export, and assembly into cyclin-CDK complexes.
- Demonstrated that Ras-dependent lung tumorigenesis is associated with increased p27 phosphorylation at S10 and its cytoplasmic mislocalization.
- Showed that p27(S10A) mice are resistant to Ras-induced tumors, as the S10A mutation prevents cytoplasmic translocation.
Conclusions:
- Phosphorylation of p27 at Serine 10 is a key regulatory event that promotes p27 cytoplasmic mislocalization and antagonizes its tumor suppressor function.
- Targeting p27 phosphorylation at S10 represents a potential therapeutic strategy for preventing or treating lung cancers driven by Ras signaling.
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