p27KIP1; cyclin-dependent kinase inhibitor 1B; cyclin-dependent kinase inhibitor p27 (CDKN1B, KIP1)
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Function
- regulator of cell cycle progression
- involved in G1 arrest
- potent inhibitor of cyclin E-CDK2 & cyclin A-CDK2 complexes
- positive regulator of cyclin D-dependent kinases such as CDK4
- regulated by phosphorylation & degradation events
- interacts with NUP50; the interaction leads to nuclear import & degradation of phosphorylated p27KIP1
- interacts with COPS5, subunit of the COP9 signalosome complex; the interaction leads to p27KIP degradation
- interacts with SPDYA in the SPDYA/CDK2/p27kip1 complex
- interacts (Thr-198 phosphorylated-form) with 14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE & YWHAH, but not YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to the cytoplasm
- interacts with AKT1, LYN & UHMK1; the interactions lead to cytoplasmic mislocation, phosphorylation of p27kip1 & inhibition of cell cycle arrest
- interacts (unphosphorylated form) with CDK2
- interacts (phosphorylated on Tyr-88 & Tyr-89) with CDK4; the interaction induces nuclear translocation
- interacts with GRB2 phosphorylated
- phosphorylation occurs on Ser, Thr & Tyr
- phosphorylation on Ser-10 is the major site of phosphorylation in resting cells, takes place at the G0-G1 phase & leads to protein stability
- phosphorylation on other sites is greatly enhanced by mitogens, growth factors, cMYC & in certain cancer cell lines
- the phosphorylated form found in the cytoplasm is inactive
- phosphorylation on Thr-198 is required for interaction with 14-3-3 proteins
- phosphorylation on Thr-187, by CDK2 leads to protein ubiquitination & proteasomal degradation; Tyr phosphorylation promotes this process
- phosphorylation by PKB/AKT1 can be suppressed by LY294002, an inhibitor of the catalytic subunit of PI3K
- phosphorylation on Tyr-88 & Tyr-89 has no effect on binding CDK2, but is required for binding CDK4
- dephosphorylated on Tyr by G-CSF
- ubiquitinated; in cytoplasm by the KPC1/KPC2 complex &, in nucleus, by SCF/SKP2 (requires prior phosphorylation on Thr-187)
- p27KIP1 & related p21WAF1/CIP1 preferentially inhibit CDK2 & CDK4-cyclin complexes[3]
- overexpression prevents entry into S phase
- p27kip1 inhibits Rb phorphorylation by cyclin E-Cdk2, cyclin A-Cdk2 & cyclin D2-Cdk4
- p27KIP1 has a region of sequence similarity to p21cip1/waf1 (pic1 protein) & is implicated in the G1 phase arrest by TGF beta, cell-cell contact, agents that elevate cAMP & the growth inhibitory drug rapamycin[4]
- AKT- or RSK-mediated phosphorylation on Thr-198, binds 14-3-3, translocates to the cytoplasm & promotes cell cycle progression
- mitogen-activated UHMK1 phosphorylation on Ser-10 also results in translocation to the cytoplasm & cell cycle progression
- phosphorylation on Ser-10 facilitates nuclear export
- translocates to the nucleus on phosphorylation of Tyr-88 & Tyr-89
Structure
- peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity
- belongs to the CDI family
Compartment
- nucleus, cytoplasm
- nuclear & cytoplasmic in quiescent cells
Expression
- expressed in all tissues tested
- highest levels in skeletal muscle, lowest in liver & kidney
- maximal levels in quiescence cells & early G1 phase
- levels decrease after mitogen stimulation as cells progress toward S-phase
Pathology
- defects in CDKN1B are the cause of multiple endocrine neoplasia 4 (MEN4)
- decreased levels of p27Kip1, mainly due to proteosomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid & prostate
Laboratory
More general terms
- nuclear protein
- anti-oncoprotein (tumor suppressor protein)
- phosphoprotein
- cyclin-dependent kinase inhibitor (CDKI, CDKN)
References
- ↑ Polyak K et al Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994 Jul 15;78(1):59-66. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8033212
- ↑ Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67-74. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8033213
- ↑ 3.0 3.1 Morgan DO. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131-4. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7877684
- ↑ 4.0 4.1 Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545-60. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7677168
- ↑ Entrez Gene http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1027
- ↑ UniProt http://www.uniprot.org/uniprot/P46527.html
- ↑ Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/CDKN1BID116.html