p27

p27, also known as p27^Kip1, is a cyclin-dependent kinase inhibitor of the Cip/Kip family. It is encoded by the CDKN1B gene in humans and consists of about 198 amino acids. p27 functions mainly to regulate the G1 to S phase transition by inhibiting cyclin-CDK complexes, particularly cyclin E-CDK2, and to a lesser extent cyclin D-CDK4/6, thereby helping to enforce cell cycle arrest in growth-restricted or differentiating cells.

Mechanism and localization. In cells preparing to proliferate, p27 binds to active cyclin-CDK complexes and blocks ATP binding and substrate phosphorylation, preventing progression into S phase. Beyond cell cycle control, p27 also participates in differentiation and can influence senescence and, in some contexts, cell migration. The subcellular distribution of p27 is dynamic and can be shifted between the nucleus and cytoplasm, which affects its ability to inhibit nuclear CDKs.

Regulation. p27 levels are governed at transcriptional and post-translational levels. A major regulatory mechanism involves the ubiquitin-proteasome system: phosphorylation of Thr187 by CDK2 targets p27 for recognition by the SCF^Skp2 E3 ligase, leading to ubiquitination and degradation as cells progress through G1. Other kinases, including AKT, can phosphorylate p27 to influence its stability and subcellular localization, often promoting cytoplasmic accumulation and reducing nuclear CDK inhibition. Interaction with Jab1/CSN5 also promotes p27 degradation.

Clinical relevance. Reduced expression or mislocalization of p27 is associated with poor prognosis in several cancers, such as breast, prostate, and pancreatic cancers, and cytoplasmic p27 localization is linked to more aggressive disease. Because p27 restrains key cell cycle kinases, its status is often examined as a marker of proliferative control and can influence therapeutic responses in oncology.