[1]
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NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 28-79 AND 104-152.
TISSUE=Kidney;
DOI=10.1016/0092-8674(94)90572-X; PubMed=8033212 [NCBI, ExPASy, EBI, Israel, Japan]
Polyak K.,
Lee M.-H.,
Erdjument-Bromage H.,
Koff A.,
Roberts J.M.,
Tempst P.,
Massague J.;
"Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.";
Cell 78:59-66(1994).
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[2]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=7882309 [NCBI, ExPASy, EBI, Israel, Japan]
Pietenpol J.A.,
Bohlander S.K.,
Sato Y.,
Papadopoulos N.,
Liu B.,
Friedman C.,
Trask B.J.,
Roberts J.M.,
Kinzler K.W.,
Rowley J.D.;
"Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias.";
Cancer Res. 55:1206-1210(1995).
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[3]
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NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-109.
Kalnine N.,
Chen X.,
Rolfs A.,
Halleck A.,
Hines L.,
Eisenstein S.,
Koundinya M.,
Raphael J.,
Moreira D.,
Kelley T.,
LaBaer J.,
Lin Y.,
Phelan M.,
Farmer A.;
"Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
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[4]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS TRP-15 AND GLY-109.
NIEHS SNPs program;
Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
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[5]
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NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-109.
TISSUE=Cervix;
DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan] The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
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[6]
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UBIQUITINATION, AND PHOSPHORYLATION.
PubMed=10323868 [NCBI, ExPASy, EBI, Israel, Japan]
Montagnoli A.,
Fiore F.,
Eytan E.,
Carrano A.C.,
Draetta G.F.,
Hershko A.,
Pagano M.;
"Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.";
Genes Dev. 13:1181-1189(1999).
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[7]
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PHOSPHORYLATION AT SER-10, AND FUNCTION.
DOI=10.1074/jbc.M001144200; PubMed=10831586 [NCBI, ExPASy, EBI, Israel, Japan]
Ishida N.,
Kitagawa M.,
Hatakeyama S.,
Nakayama K.;
"Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability.";
J. Biol. Chem. 275:25146-25154(2000).
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[8]
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INTERACTION WITH UHMK1, PHOSPHORYLATION AT SER-10, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-10 AND THR-187.
DOI=10.1093/emboj/cdf343; PubMed=12093740 [NCBI, ExPASy, EBI, Israel, Japan]
Boehm M.,
Yoshimoto T.,
Crook M.F.,
Nallamshetty S.,
True A.,
Nabel G.J.,
Nabel E.G.;
"A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression.";
EMBO J. 21:3390-3401(2002).
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[9]
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PHOSPHORYLATION AT SER-10; THR-187 AND THR-198, INTERACTION WITH AKT1 AND YWHAQ, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-10; THR-157; THR-187 AND THR-198.
DOI=10.1074/jbc.M203668200; PubMed=12042314 [NCBI, ExPASy, EBI, Israel, Japan]
Fujita N.,
Sato S.,
Katayama K.,
Tsuruo T.;
"Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization.";
J. Biol. Chem. 277:28706-28713(2002).
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[10]
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PHOSPHORYLATION AT THR-157, SUBCELLULAR LOCATION, ASSOCIATED WITH BREAST CANCER, AND MUTAGENESIS OF THR-157.
DOI=10.1038/nm762; PubMed=12244303 [NCBI, ExPASy, EBI, Israel, Japan]
Viglietto G.,
Motti M.L.,
Bruni P.,
Melillo R.M.,
D'Alessio A.,
Califano D.,
Vinci F.,
Chiappetta G.,
Tsichlis P.,
Bellacosa A.,
Fusco A.,
Santoro M.;
"Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.";
Nat. Med. 8:1136-1144(2002).
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[11]
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PHOSPHORYLATION AT THR-157, INTERACTION WITH AKT1, SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS OF THR-157; SER-161 AND THR-162.
DOI=10.1038/nm759; PubMed=12244301 [NCBI, ExPASy, EBI, Israel, Japan]
Shin I.,
Yakes F.M.,
Rojo F.,
Shin N.-Y.,
Bakin A.V.,
Baselga J.,
Arteaga C.L.;
"PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization.";
Nat. Med. 8:1145-1152(2002).
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[12]
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PHOSPHORYLATION AT SER-10 AND THR-198, INTERACTION WITH YWHAE; YWHAH; SFN; YWHAQ; RPS6KA4 AND RPS6KA5, SUBCELLULAR LOCATION, AND MUTAGENESIS OF THR-157 AND THR-198.
DOI=10.1074/jbc.M306614200; PubMed=14504289 [NCBI, ExPASy, EBI, Israel, Japan]
Fujita N.,
Sato S.,
Tsuruo T.;
"Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization.";
J. Biol. Chem. 278:49254-49260(2003).
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[13]
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INTERACTION WITH SPDYA.
DOI=10.1091/mbc.E02-12-0820; PubMed=12972555 [NCBI, ExPASy, EBI, Israel, Japan]
Porter L.A.,
Kong-Beltran M.,
Donoghue D.J.;
"Spy1 interacts with p27Kip1 to allow G1/S progression.";
Mol. Biol. Cell 14:3664-3674(2003).
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[14]
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PHOSPHORYLATION AT THR-198, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-10; THR-157; THR-187 AND THR-198.
PubMed=15280662 [NCBI, ExPASy, EBI, Israel, Japan]
Motti M.L.,
De Marco C.,
Califano D.,
Fusco A.,
Viglietto G.;
"Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer.";
Cell Cycle 3:1074-1080(2004).
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[15]
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PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, AND MASS SPECTROMETRY.
TISSUE=Epithelium;
DOI=10.1073/pnas.0404720101; PubMed=15302935 [NCBI, ExPASy, EBI, Israel, Japan]
Beausoleil S.A.,
Jedrychowski M.,
Schwartz D.,
Elias J.E.,
Villen J.,
Li J.,
Cohn M.A.,
Cantley L.C.,
Gygi S.P.;
"Large-scale characterization of HeLa cell nuclear phosphoproteins.";
Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004).
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[16]
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PHOSPHORYLATION AT TYR-88 AND TYR-89, DEPHOSPHORYLATION, INTERACTION WITH GRB2; CDK2 AND CDK4, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-74; TYR-88 AND TYR-89.
DOI=10.1182/blood-2005-05-1771; PubMed=16195327 [NCBI, ExPASy, EBI, Israel, Japan]
Kardinal C.,
Dangers M.,
Kardinal A.,
Koch A.,
Brandt D.T.,
Tamura T.,
Welte K.;
"Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4.";
Blood 107:1133-1140(2006).
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[17]
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ASSOCIATION WITH MEN4.
DOI=10.1073/pnas.0603877103; PubMed=17030811 [NCBI, ExPASy, EBI, Israel, Japan]
Pellegata N.S.,
Quintanilla-Martinez L.,
Siggelkow H.,
Samson E.,
Bink K.,
Hoefler H.,
Fend F.,
Graw J.,
Atkinson M.J.;
"Germ-line mutations in p27(Kip1) cause a multiple endocrine neoplasia syndrome in rats and humans.";
Proc. Natl. Acad. Sci. U.S.A. 103:15558-15563(2006).
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[18]
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PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-140, AND MASS SPECTROMETRY.
DOI=10.1126/science.1140321; PubMed=17525332 [NCBI, ExPASy, EBI, Israel, Japan]
Matsuoka S.,
Ballif B.A.,
Smogorzewska A.,
McDonald E.R. III,
Hurov K.E.,
Luo J.,
Bakalarski C.E.,
Zhao Z.,
Solimini N.,
Lerenthal Y.,
Shiloh Y.,
Gygi S.P.,
Elledge S.J.;
"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.";
Science 316:1160-1166(2007).
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[19]
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X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 23-106 OF COMPLEX WITH CDK2 AND CG2A.
DOI=10.1038/382325a0; PubMed=8684460 [NCBI, ExPASy, EBI, Israel, Japan]
Russo A.A.,
Jeffrey P.D.,
Patten A.K.,
Massague J.,
Pavletich N.P.;
"Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex.";
Nature 382:325-331(1996).
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[20]
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STRUCTURE BY NMR OF 22-104, PHOSPHORYLATION AT TYR-88, FUNCTION, INDUCTION, INTERACTION WITH LYN, MASS SPECTROMETRY, AND MUTAGENESIS OF TYR-88 AND TYR-89.
DOI=10.1016/j.cell.2006.11.047; PubMed=17254966 [NCBI, ExPASy, EBI, Israel, Japan]
Grimmler M.,
Wang Y.,
Mund T.,
Cilensek Z.,
Keidel E.-M.,
Waddell M.B.,
Jaekel H.,
Kullmann M.,
Kriwacki R.W.,
Hengst L.;
"Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases.";
Cell 128:269-280(2007).
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- FUNCTION: Important regulator of cell cycle progrssion. Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Positive regulator of cyclin D-dependent kinases such as CDK4. Regulated by phosphorylation and degradation events.
- SUBUNIT: Interacts with NUP50; the interaction leads to nuclear import and 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 and YWHAH, but not YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to the cytoplasm. Interacts with AKT1, LYN and UHMK1; the interactions lead to cytoplasmic mislocation, phosphorylation of p27kip1 and inhibition of cell cycle arrest. Interacts (unphosphorylated form) with CDK2. Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the interaction induces nuclear translocation. Interacts with GRB2.
- INTERACTION:
P00520:Abl1 (xeno); NbExp=1; IntAct=EBI-519280, EBI-914519;
P20248:CCNA2; NbExp=4; IntAct=EBI-519280, EBI-457097;
P14635:CCNB1; NbExp=1; IntAct=EBI-519280, EBI-495332;
P24385:CCND1; NbExp=2; IntAct=EBI-519280, EBI-375001;
P24864:CCNE1; NbExp=2; IntAct=EBI-519280, EBI-519526;
O96020:CCNE2; NbExp=1; IntAct=EBI-519280, EBI-375033;
P24941:CDK2; NbExp=6; IntAct=EBI-519280, EBI-375096;
P11802:CDK4; NbExp=2; IntAct=EBI-519280, EBI-295644;
Q00535:CDK5; NbExp=2; IntAct=EBI-519280, EBI-1041567;
Q92905:COPS5; NbExp=1; IntAct=EBI-519280, EBI-594661;
O00505:KPNA3; NbExp=1; IntAct=EBI-519280, EBI-358297;
O15131:KPNA5; NbExp=3; IntAct=EBI-519280, EBI-540602;
P07948:LYN; NbExp=2; IntAct=EBI-519280, EBI-79452;
P12931:SRC; NbExp=1; IntAct=EBI-519280, EBI-621482;
P16949:STMN1; NbExp=1; IntAct=EBI-519280, EBI-445909;
P09936:UCHL1; NbExp=1; IntAct=EBI-519280, EBI-714860;
P07947:YES1; NbExp=1; IntAct=EBI-519280, EBI-515331;
P31946:YWHAB; NbExp=1; IntAct=EBI-519280, EBI-359815;
P62258:YWHAE; NbExp=1; IntAct=EBI-519280, EBI-356498;
P61981:YWHAG; NbExp=1; IntAct=EBI-519280, EBI-359832;
- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Note=Nuclear and cytoplasmic in quiescent cells. AKT- or RSK-mediated phosphorylation on Thr-198, binds 14-3-3, translocates to the cytoplasm and promotes cell cycle progression. Mitogen-activated UHMK1 phosphorylation on Ser-10 also results in translocation to the cytoplasm and cell cycle progression. Phosphorylation on Ser-10 facilitates nuclear export. Translocates to the nucleus on phosphorylation of Tyr-88 and Tyr-89.
- TISSUE SPECIFICITY: Expressed in all tissues tested. Highest levels in skeletal muscle, lowest in liver and kidney.
- INDUCTION: Maximal levels in quiescence cells and early G(1). Levels decrease after mitogen stimulation as cells progress toward S-phase.
- DOMAIN: A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity.
- PTM: Phosphorylated; phosphorylation occurs on serine, threonine and tyrosine residues. Phosphorylation on Ser-10 is the major site of phosphorylation in resting cells, takes place at the G(0)-G(1) phase and leads to protein stability. Phosphorylation on other sites is greatly enhanced by mitogens, growth factors, cMYC and in certain cancer cell lines. The phosphorylated form found in the cytoplasm is inactivate. Phosphorylation on Thr-198 is required for interaction with 14-3-3 proteins. Phosphorylation on Thr-187, by CDK2 leads to protein ubiquitination and proteasomal degradation. Tyrosine 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 and Tyr-89 has no effect on binding CDK2, but is required for binding CDK4. Dephosphorylated on tyrosine residues by G-CSF.
- PTM: Ubiquitinated; in the cytoplasm by the KPC1/KPC2 complex and, in the nucleus, by SCF/SKP2. The latter requires prior phosphorylation on Thr-187.
- DISEASE: Defects in CDKN1B are the cause of multiple endocrine neoplasia type 4 (MEN4) [MIM:610755]. Multiple endocrine neoplasia (MEN) syndromes are inherited cancer syndromes of the thyroid. MEN4 is a MEN-like syndrome with a phenotypic overlap of both MEN1 and MEN2.
- MISCELLANEOUS: Decreased levels of p27Kip1, mainly due to proteosomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid and prostate.
- SIMILARITY: Belongs to the CDI family.
- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/CDKN1BID116.html";.
- WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/cdkn1b/";.
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