to begin progressing through the cell cycle. Transcription 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 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. Proteolysis 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. Nuclear export 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