p27Kip1

p27Kip1, also known as p27, is a member of the CIP/KIP family of cyclin-dependent kinase inhibitors. In humans it is encoded by the CDKN1B gene. p27 inhibits cyclin-CDK complexes, most notably cyclin E–CDK2, thereby restraining the cell cycle at the G1 phase. Depending on context, it can also interact with cyclin D–CDK4/6 and influence their activity, but its primary function is to enforce G1 arrest in response to anti-proliferative signals.

Regulation of p27 occurs at multiple levels. The protein is controlled transcriptionally and translationally, and its stability is governed by the ubiquitin–proteasome system. Phosphorylation by CDK2 on T187 promotes recognition by the SCF-Skp2 ubiquitin ligase, targeting p27 for degradation as cells progress through late G1 and into S phase. Other phosphorylation events, including those mediated by AKT or ERK pathways, can promote cytoplasmic localization by masking nuclear localization signals, reducing p27’s nuclear CDK-inhibitory activity. p27 is predominantly nuclear, but cytoplasmic p27 is frequently observed in cancers and is associated with altered function.

Biological roles extend beyond cell cycle control. In addition to enforcing G1 arrest, p27 participates in differentiation, senescence, and the maintenance of stem cell quiescence. Noncanonical roles in the cytoplasm include modulation of cell migration and interactions with signaling pathways, such as effects on RhoA activity, and potential involvement in DNA repair and autophagy.

Clinical significance of p27 includes its frequent alteration in cancer. Reduced p27 expression or cytoplasmic mislocalization often correlates with tumor progression and poorer prognosis, though the relationship can vary by cancer type. p27 is studied as a prognostic and, in some contexts, a predictive biomarker and therapeutic target.