CLONING OF P27(KIP1), A CYCLIN-DEPENDENT KINASE INHIBITOR AND A POTENTIAL MEDIATOR OF EXTRACELLULAR ANTIMITOGENIC SIGNALS

We cloned p27(Kip1), a cyclin-dependent kinase inhibitor implicated in G1 phase arrest by TGF beta and cell-cell contact. p27(Kip1) associat es with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their a ctivation, and inhibits previously activated complexes, and p27(Kip1) overexpression obstructs cell entry into S phase. p27(Kip1) potently i nhibits Rb phosphorylation by cyclin E-Cdk2, cyclin A-Cdk2, and cyclin D2-Cdk4. p27(Kip1) is highly conserved and broadly expressed in human tissues, and its mRNA levels are similar in proliferating and quiesce nt cells. p27(Kip1) has a region of sequence similarity to p21(Cip1/WA F1), the Cdk inhibitor whose transcription is stimulated by p53. A p27 (Kip1) peptide corresponding to this region retains Cdk inhibitory act ivity. We suggest that cell contact, TGF beta, and p53 all restrain ce ll proliferation through related Cdk inhibitors.