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p27(Kip1) signaling: Transcriptional and post-translational regulation

Su Su Thae Hnit1, Chanlu Xie1, Mu Yao2

  • 1School of Science and Health, University of Western Sydney, Australia.

The International Journal of Biochemistry & Cell Biology
|August 18, 2015
PubMed

Insights

p27(Kip1) protein levels are crucial for cancer progression. Therapies targeting p27(Kip1) localization and degradation could inhibit cancer cell cycle entry and progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • p27(Kip1) is a cyclin-dependent kinase (CDK) inhibitor; its downregulation correlates with cancer progression and poor prognosis.
  • MENIN positively regulates p27(Kip1) expression, while MYC and PIM inhibit it.
  • Post-translational modifications, particularly phosphorylation, heavily influence p27(Kip1) protein stability, localization, and degradation.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of p27(Kip1) protein levels and function.
  • To identify potential therapeutic strategies for cancer by modulating p27(Kip1).

Main Methods:

  • The study focuses on the post-translational modifications of p27(Kip1), including phosphorylation.
  • Investigates the roles of E3 ubiquitin ligases (SKP2, KPC, PIRH2) and CRM1 in p27(Kip1) degradation and localization.
  • Examines the impact of phosphorylation at Thr(187) and Ser(10) on p27(Kip1) stability and cellular compartment.

Main Results:

  • Phosphorylation of p27(Kip1) at Thr(187) and Ser(10) targets it for degradation by SKP2 and KPC, respectively.
  • Ser(10) phosphorylation promotes cytoplasmic localization of p27(Kip1) via CRM1-mediated nuclear export.
  • PIRH2 mediates p27(Kip1) degradation independently of its phosphorylation status in both cytoplasm and nucleus.

Conclusions:

  • p27(Kip1) degradation and localization are tightly regulated by post-translational modifications and specific E3 ubiquitin ligases.
  • Targeting p27(Kip1) degradation pathways and correcting its cellular localization represent promising therapeutic strategies for inhibiting cancer cell proliferation.
Keywords:
CRM1KPCMYCPIRH2SKP2p27(Kip1)

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