P27

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle. The p27Kip1 gene has a DNA sequence similar to other members of the "Cip/Kip" family which include the p21Cip1/Waf1 and p57Kip2 genes. In addition to this structural similarity the "Cip/Kip" proteins share the functional characteristic of being able to bind several different classes of Cyclin and Cdk molecules. For example, p27Kip1 binds to cyclin D either alone, or when complexed to its catalytic subunit CDK4. In doing so p27Kip1 inhibits the catalytic activity of Cdk4, which means that it prevents Cdk4 from adding phosphate residues to its principal substrate, the retinoblastoma (pRb) protein. Increased levels of the p27Kip1 protein typically cause cells to arrest in the G1 phase of the cell cycle. Likewise, p27Kip1 is able to bind other Cdk proteins when complexed to cyclin subunits such as Cyclin E/Cdk2 and Cyclin A/Cdk2. In general, extracellular growth factors which promote cell division reduce transcription and translation of p27Kip1. Also, increased synthesis of CDk4,6/cyclin D causes binding of p27 to this complex, sequestering it from binding to the CDk2/cyclin E complex. Furthermore, an active CDK2/cyclin E complex will phosphorylate p27 and tag p27 for ubiquitination. A mutation of this gene may lead to loss of control over the cell cycle leading to uncontrolled cellular proliferation. Loss of p27 expression has been observed in metastatic canine mammary carcinomas. Decreased TGF-beta signalling has been suggested to cause loss of p27 expression in this tumor type.