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p27/Kip1 regulates the cell cycle by inhibiting the checkpoint kinase cdk2/cyclin E and blocking cell cycle progression through the G1-S transition. Cancer cells in some cases have reduced levels of p27, supporting the importance of p27 in cell cycle regulation. The activity of p27 is regulated by phosphorylation, synthesis and degradation. Phosphorylation of p27 at threonine-187 by cdk2 causes p27 to associate with an SCF complex that targets p27 for proteolytic degradation. The F box protein Skp2 binds specifically to threonine-187 phosphorylated p27, recruiting it to the SCF complex for degradation. Other components of the p27 ubiquitin ligase complex include Skp1, Cul1, and Roc1/Rbx-1. Cks-1 has also been identified in a reconstituted system as an essential component for recruitment of p27 for degradation by the SCF complex. Signaling by cytokines may modulate cell survival, proliferation, or apoptosis through modulation of p27 expression. Cytokine and AKT signaling pathways activate forkhead transcription factors that induce p27 expression at the transcriptional level. |
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Carrano, A.C. et al. (1999) SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat. Cell. Biol. 1(4), 193-9
Dijkers, P.F., (2000) Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol. Cell. Biol. 20(24), 9138-48
Ganoth, D. et al. (2001) The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27. Nat. Cell. Biol. 3(3), 321-4
Malek, N.P. et al. (2001) A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413(6853), 323-7
Podust, V.N. et al. (2000) A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination. Proc Natl Acad Sci U S A 97(9), 4579-84
Vladimir N. Podust, et al. A Nedd8 Conjugation Pathway is Essential for Proteolytic Targeting of p27^Kip1 by Ubiquitination. PNAS, Vol 97, April 2000, 4579-4584.
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