CDKN1B

2AST, 1H27, 1JSU102712576ENSG00000111276ENSMUSG00000003031P46527P46414NM_004064NM_009875NP_004055NP_034005Cyclin-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.1jsu: P27(KIP1)/CYCLIN A/CDK2 COMPLEX 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. A structured cis-regulatory element has been found in the 5' UTR of the P27 mRNA where it is thought to regulate translation relative to cell cycle progression. P27 regulation is accomplished by two different mechanisms. In the first its concentration is changed by the individual rates of transcription, translation, and proteolysis. P27 can also be regulated by changing its subcellular location Both mechanisms act to reduce levels of p27, allowing for the activation of Cdk1 and Cdk2, and for the cell to begin progressing through the cell cycle. Transcription of the CDKN1B gene is activated by Forkhead box class O family (FoxO) proteins which also acts downstream to promote p27 nuclear localization and decrease levels of COP9 subunit 5(COPS5) which helps in the degradation of p27. Transcription for p27 is activated by FoxO in response to cytokines, promyelocytic leukaemia proteins, and nuclear Akt signaling. P27 transcription has also been linked to another tumor suppressor gene, MEN1, in pancreatic islet cells where it promotes CDKN1B expression. Translation of CDKN1B reaches its maximum during quiescence and early G1. Translation is regulated by polypyrimidine tract-binding protein(PTB), ELAVL1, ELAVL4, and microRNAs. PTB acts by binding CDKN1b IRES to increase translation and when PTB levels decrease, G1 phase is shortened. ELAVL1 and ELAVL4 also bind to CDKN1B IRES but they do so in order to decrease translation and so depletion of either results in G1 arrest. Degradation of the p27 protein occurs as cells exit quiescence and enter G1. Protein levels continue to fall rapidly as the cell continues through G1 and enters S phase. One of the most understood mechanisms for p27 proteolysis is the polyubiquitylation of p27 by the SCFSKP2 kinase associated protein 1 (Skp1) and 2 (Skp2). SKP1 and Skp2 degrades p27 after it has been phosphorylated at threonine 187 (Thr187) by either activating cyclin E- or cyclin A-CDK2. Skp2 is mainly responsible for the degradation of p27 levels that continues through S phase. However it is rarely expressed in early G1 where p27 levels first begin to decrease. During early G1 proteolysis of p27 is regulated by KIP1 Ubiquitylation Promoting Complex (KPC) which binds to its CDK inhibitory domain. P27 also has three Cdk-inhibited tyrosines at residues 74, 88, and 89. Of these, Tyr74 is of special interest because it is specific to p27-type inhibitors. Alternatively to the transcription, translation, and protelytic method of regulation, p27 levels can also be changed by exporting p27 to the cytoplasm. This occurs when p27 is phosphorylated on Ser(10) which allows for CRM1, a nuclear export carrier protein, to bind to and remove p27 from the nucleus. Once p27 is excluded from the nucleus it cannot inhibit the cell’s growth. In the cytoplasm it may be degraded entirely or retained. This step occurs very early when the cell is exiting the quiescent phase and thus is independent of Skp2 degradation of p27.