Full text data of CDKN2C
CDKN2C
(CDKN6)
[Confidence: low (only semi-automatic identification from reviews)]
Cyclin-dependent kinase 4 inhibitor C (Cyclin-dependent kinase 6 inhibitor; p18-INK4c; p18-INK6)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Cyclin-dependent kinase 4 inhibitor C (Cyclin-dependent kinase 6 inhibitor; p18-INK4c; p18-INK6)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P42773
ID CDN2C_HUMAN Reviewed; 168 AA.
AC P42773; Q8TB83;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=Cyclin-dependent kinase 4 inhibitor C;
DE AltName: Full=Cyclin-dependent kinase 6 inhibitor;
DE AltName: Full=p18-INK4c;
DE AltName: Full=p18-INK6;
GN Name=CDKN2C; Synonyms=CDKN6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8001816;
RA Guan K.-L., Jenkins C.W., Li Y., Nichols M.A., Wu X., O'Keefe C.L.,
RA Matera G.A., Xiong Y.;
RT "Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related
RT CDK6 inhibitor, correlates with wild-type pRb function.";
RL Genes Dev. 8:2939-2952(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT BREAST CANCER
RP PRO-72.
RC TISSUE=Mammary gland;
RX PubMed=9636670; DOI=10.1006/bbrc.1998.8497;
RA Blais A., Labrie Y., Pouliot F., Lachance Y., Labrie C.;
RT "Structure of the gene encoding the human cyclin-dependent kinase
RT inhibitor p18 and mutational analysis in breast cancer.";
RL Biochem. Biophys. Res. Commun. 247:146-153(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-126.
RC TISSUE=Brain, Kidney, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
RX PubMed=9437433; DOI=10.1038/nsb0198-74;
RA Venkataramani R., Swaminathan K., Marmorstein R.;
RT "Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides
RT insights into ankyrin-like repeat structure/function and tumor-derived
RT p16INK4 mutations.";
RL Nat. Struct. Biol. 5:74-81(1998).
RN [7]
RP STRUCTURE BY NMR.
RX PubMed=10074345; DOI=10.1021/bi982286e;
RA Li J., Byeon I.-J.L., Ericson K., Poi M.-J., O'Maille P., Selby T.,
RA Tsai M.-D.;
RT "Tumor suppressor INK4: determination of the solution structure of
RT p18INK4C and demonstration of the functional significance of loops in
RT p18INK4C and p16INK4A.";
RL Biochemistry 38:2930-2940(1999).
RN [8]
RP VARIANT BREAST CANCER PRO-72.
RX PubMed=8840966;
RA Lapointe J., Lachance Y., Labrie Y., Labrie C.;
RT "A p18 mutant defective in CDK6 binding in human breast cancer
RT cells.";
RL Cancer Res. 56:4586-4589(1996).
CC -!- FUNCTION: Interacts strongly with CDK6, weakly with CDK4. Inhibits
CC cell growth and proliferation with a correlated dependence on
CC endogenous retinoblastoma protein RB.
CC -!- SUBUNIT: Heterodimer of p18 with CDK6.
CC -!- INTERACTION:
CC P11802:CDK4; NbExp=3; IntAct=EBI-711290, EBI-295644;
CC Q00534:CDK6; NbExp=3; IntAct=EBI-711290, EBI-295663;
CC -!- TISSUE SPECIFICITY: Highest levels found in skeletal muscle. Also
CC found in pancreas and heart.
CC -!- SIMILARITY: Belongs to the CDKN2 cyclin-dependent kinase inhibitor
CC family.
CC -!- SIMILARITY: Contains 4 ANK repeats.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/cdkn2c/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U17074; AAC50074.1; -; mRNA.
DR EMBL; AF041248; AAC39782.1; -; mRNA.
DR EMBL; AF041250; AAC39783.1; -; Genomic_DNA.
DR EMBL; AF041249; AAC39783.1; JOINED; Genomic_DNA.
DR EMBL; AY094608; AAM11873.1; -; Genomic_DNA.
DR EMBL; BC000598; AAH00598.1; -; mRNA.
DR EMBL; BC005041; AAH05041.1; -; mRNA.
DR EMBL; BC016173; AAH16173.1; -; mRNA.
DR PIR; A55479; A55479.
DR RefSeq; NP_001253.1; NM_001262.2.
DR RefSeq; NP_523240.1; NM_078626.2.
DR UniGene; Hs.525324; -.
DR PDB; 1BU9; NMR; -; A=1-168.
DR PDB; 1G3N; X-ray; 2.90 A; B/F=1-168.
DR PDB; 1IHB; X-ray; 1.95 A; A/B=1-162.
DR PDB; 1MX2; X-ray; 2.25 A; A/B=1-168.
DR PDB; 1MX4; X-ray; 2.00 A; A/B=1-168.
DR PDB; 1MX6; X-ray; 2.00 A; A/B=1-168.
DR PDBsum; 1BU9; -.
DR PDBsum; 1G3N; -.
DR PDBsum; 1IHB; -.
DR PDBsum; 1MX2; -.
DR PDBsum; 1MX4; -.
DR PDBsum; 1MX6; -.
DR ProteinModelPortal; P42773; -.
DR SMR; P42773; 5-160.
DR IntAct; P42773; 16.
DR MINT; MINT-1372629; -.
DR STRING; 9606.ENSP00000262662; -.
DR PhosphoSite; P42773; -.
DR DMDM; 1168870; -.
DR PaxDb; P42773; -.
DR PRIDE; P42773; -.
DR DNASU; 1031; -.
DR Ensembl; ENST00000262662; ENSP00000262662; ENSG00000123080.
DR Ensembl; ENST00000371761; ENSP00000360826; ENSG00000123080.
DR Ensembl; ENST00000396148; ENSP00000379452; ENSG00000123080.
DR GeneID; 1031; -.
DR KEGG; hsa:1031; -.
DR UCSC; uc001csf.3; human.
DR CTD; 1031; -.
DR GeneCards; GC01P051427; -.
DR HGNC; HGNC:1789; CDKN2C.
DR HPA; CAB005303; -.
DR HPA; CAB018398; -.
DR HPA; HPA019057; -.
DR HPA; HPA019764; -.
DR MIM; 603369; gene.
DR neXtProt; NX_P42773; -.
DR Orphanet; 652; Multiple endocrine neoplasia type 1.
DR PharmGKB; PA26322; -.
DR eggNOG; COG0666; -.
DR HOGENOM; HOG000290191; -.
DR HOVERGEN; HBG050870; -.
DR InParanoid; P42773; -.
DR KO; K06622; -.
DR OMA; LMKHTAC; -.
DR OrthoDB; EOG7ZSHVC; -.
DR PhylomeDB; P42773; -.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_120956; Cellular responses to stress.
DR EvolutionaryTrace; P42773; -.
DR GeneWiki; CDKN2C; -.
DR GenomeRNAi; 1031; -.
DR NextBio; 4337; -.
DR PRO; PR:P42773; -.
DR ArrayExpress; P42773; -.
DR Bgee; P42773; -.
DR CleanEx; HS_CDKN2C; -.
DR Genevestigator; P42773; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0007050; P:cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IDA:BHF-UCL.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IEA:Ensembl.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; IDA:BHF-UCL.
DR Gene3D; 1.25.40.20; -; 2.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR Pfam; PF00023; Ank; 3.
DR SMART; SM00248; ANK; 4.
DR SUPFAM; SSF48403; SSF48403; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 2.
PE 1: Evidence at protein level;
KW 3D-structure; ANK repeat; Cell cycle; Complete proteome; Polymorphism;
KW Reference proteome; Repeat.
FT CHAIN 1 168 Cyclin-dependent kinase 4 inhibitor C.
FT /FTId=PRO_0000144186.
FT REPEAT 4 33 ANK 1.
FT REPEAT 37 65 ANK 2.
FT REPEAT 69 98 ANK 3.
FT REPEAT 102 132 ANK 4.
FT VARIANT 72 72 A -> P (in breast cancer; loss of CDK6
FT interaction).
FT /FTId=VAR_001490.
FT VARIANT 126 126 T -> M (in dbSNP:rs17851380).
FT /FTId=VAR_038604.
FT HELIX 6 15
FT HELIX 18 24
FT TURN 36 38
FT HELIX 41 44
FT TURN 45 48
FT HELIX 50 58
FT HELIX 73 80
FT HELIX 83 91
FT STRAND 101 103
FT HELIX 106 112
FT HELIX 116 125
FT STRAND 135 137
FT HELIX 140 146
FT HELIX 150 158
SQ SEQUENCE 168 AA; 18127 MW; 5D66AFA715186E9A CRC64;
MAEPWGNELA SAAARGDLEQ LTSLLQNNVN VNAQNGFGRT ALQVMKLGNP EIARRLLLRG
ANPDLKDRTG FAVIHDAARA GFLDTLQTLL EFQADVNIED NEGNLPLHLA AKEGHLRVVE
FLVKHTASNV GHRNHKGDTA CDLARLYGRN EVVSLMQANG AGGATNLQ
//
ID CDN2C_HUMAN Reviewed; 168 AA.
AC P42773; Q8TB83;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=Cyclin-dependent kinase 4 inhibitor C;
DE AltName: Full=Cyclin-dependent kinase 6 inhibitor;
DE AltName: Full=p18-INK4c;
DE AltName: Full=p18-INK6;
GN Name=CDKN2C; Synonyms=CDKN6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8001816;
RA Guan K.-L., Jenkins C.W., Li Y., Nichols M.A., Wu X., O'Keefe C.L.,
RA Matera G.A., Xiong Y.;
RT "Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related
RT CDK6 inhibitor, correlates with wild-type pRb function.";
RL Genes Dev. 8:2939-2952(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT BREAST CANCER
RP PRO-72.
RC TISSUE=Mammary gland;
RX PubMed=9636670; DOI=10.1006/bbrc.1998.8497;
RA Blais A., Labrie Y., Pouliot F., Lachance Y., Labrie C.;
RT "Structure of the gene encoding the human cyclin-dependent kinase
RT inhibitor p18 and mutational analysis in breast cancer.";
RL Biochem. Biophys. Res. Commun. 247:146-153(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-126.
RC TISSUE=Brain, Kidney, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
RX PubMed=9437433; DOI=10.1038/nsb0198-74;
RA Venkataramani R., Swaminathan K., Marmorstein R.;
RT "Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides
RT insights into ankyrin-like repeat structure/function and tumor-derived
RT p16INK4 mutations.";
RL Nat. Struct. Biol. 5:74-81(1998).
RN [7]
RP STRUCTURE BY NMR.
RX PubMed=10074345; DOI=10.1021/bi982286e;
RA Li J., Byeon I.-J.L., Ericson K., Poi M.-J., O'Maille P., Selby T.,
RA Tsai M.-D.;
RT "Tumor suppressor INK4: determination of the solution structure of
RT p18INK4C and demonstration of the functional significance of loops in
RT p18INK4C and p16INK4A.";
RL Biochemistry 38:2930-2940(1999).
RN [8]
RP VARIANT BREAST CANCER PRO-72.
RX PubMed=8840966;
RA Lapointe J., Lachance Y., Labrie Y., Labrie C.;
RT "A p18 mutant defective in CDK6 binding in human breast cancer
RT cells.";
RL Cancer Res. 56:4586-4589(1996).
CC -!- FUNCTION: Interacts strongly with CDK6, weakly with CDK4. Inhibits
CC cell growth and proliferation with a correlated dependence on
CC endogenous retinoblastoma protein RB.
CC -!- SUBUNIT: Heterodimer of p18 with CDK6.
CC -!- INTERACTION:
CC P11802:CDK4; NbExp=3; IntAct=EBI-711290, EBI-295644;
CC Q00534:CDK6; NbExp=3; IntAct=EBI-711290, EBI-295663;
CC -!- TISSUE SPECIFICITY: Highest levels found in skeletal muscle. Also
CC found in pancreas and heart.
CC -!- SIMILARITY: Belongs to the CDKN2 cyclin-dependent kinase inhibitor
CC family.
CC -!- SIMILARITY: Contains 4 ANK repeats.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/cdkn2c/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U17074; AAC50074.1; -; mRNA.
DR EMBL; AF041248; AAC39782.1; -; mRNA.
DR EMBL; AF041250; AAC39783.1; -; Genomic_DNA.
DR EMBL; AF041249; AAC39783.1; JOINED; Genomic_DNA.
DR EMBL; AY094608; AAM11873.1; -; Genomic_DNA.
DR EMBL; BC000598; AAH00598.1; -; mRNA.
DR EMBL; BC005041; AAH05041.1; -; mRNA.
DR EMBL; BC016173; AAH16173.1; -; mRNA.
DR PIR; A55479; A55479.
DR RefSeq; NP_001253.1; NM_001262.2.
DR RefSeq; NP_523240.1; NM_078626.2.
DR UniGene; Hs.525324; -.
DR PDB; 1BU9; NMR; -; A=1-168.
DR PDB; 1G3N; X-ray; 2.90 A; B/F=1-168.
DR PDB; 1IHB; X-ray; 1.95 A; A/B=1-162.
DR PDB; 1MX2; X-ray; 2.25 A; A/B=1-168.
DR PDB; 1MX4; X-ray; 2.00 A; A/B=1-168.
DR PDB; 1MX6; X-ray; 2.00 A; A/B=1-168.
DR PDBsum; 1BU9; -.
DR PDBsum; 1G3N; -.
DR PDBsum; 1IHB; -.
DR PDBsum; 1MX2; -.
DR PDBsum; 1MX4; -.
DR PDBsum; 1MX6; -.
DR ProteinModelPortal; P42773; -.
DR SMR; P42773; 5-160.
DR IntAct; P42773; 16.
DR MINT; MINT-1372629; -.
DR STRING; 9606.ENSP00000262662; -.
DR PhosphoSite; P42773; -.
DR DMDM; 1168870; -.
DR PaxDb; P42773; -.
DR PRIDE; P42773; -.
DR DNASU; 1031; -.
DR Ensembl; ENST00000262662; ENSP00000262662; ENSG00000123080.
DR Ensembl; ENST00000371761; ENSP00000360826; ENSG00000123080.
DR Ensembl; ENST00000396148; ENSP00000379452; ENSG00000123080.
DR GeneID; 1031; -.
DR KEGG; hsa:1031; -.
DR UCSC; uc001csf.3; human.
DR CTD; 1031; -.
DR GeneCards; GC01P051427; -.
DR HGNC; HGNC:1789; CDKN2C.
DR HPA; CAB005303; -.
DR HPA; CAB018398; -.
DR HPA; HPA019057; -.
DR HPA; HPA019764; -.
DR MIM; 603369; gene.
DR neXtProt; NX_P42773; -.
DR Orphanet; 652; Multiple endocrine neoplasia type 1.
DR PharmGKB; PA26322; -.
DR eggNOG; COG0666; -.
DR HOGENOM; HOG000290191; -.
DR HOVERGEN; HBG050870; -.
DR InParanoid; P42773; -.
DR KO; K06622; -.
DR OMA; LMKHTAC; -.
DR OrthoDB; EOG7ZSHVC; -.
DR PhylomeDB; P42773; -.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_120956; Cellular responses to stress.
DR EvolutionaryTrace; P42773; -.
DR GeneWiki; CDKN2C; -.
DR GenomeRNAi; 1031; -.
DR NextBio; 4337; -.
DR PRO; PR:P42773; -.
DR ArrayExpress; P42773; -.
DR Bgee; P42773; -.
DR CleanEx; HS_CDKN2C; -.
DR Genevestigator; P42773; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0007050; P:cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IDA:BHF-UCL.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IEA:Ensembl.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; IDA:BHF-UCL.
DR Gene3D; 1.25.40.20; -; 2.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR Pfam; PF00023; Ank; 3.
DR SMART; SM00248; ANK; 4.
DR SUPFAM; SSF48403; SSF48403; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 2.
PE 1: Evidence at protein level;
KW 3D-structure; ANK repeat; Cell cycle; Complete proteome; Polymorphism;
KW Reference proteome; Repeat.
FT CHAIN 1 168 Cyclin-dependent kinase 4 inhibitor C.
FT /FTId=PRO_0000144186.
FT REPEAT 4 33 ANK 1.
FT REPEAT 37 65 ANK 2.
FT REPEAT 69 98 ANK 3.
FT REPEAT 102 132 ANK 4.
FT VARIANT 72 72 A -> P (in breast cancer; loss of CDK6
FT interaction).
FT /FTId=VAR_001490.
FT VARIANT 126 126 T -> M (in dbSNP:rs17851380).
FT /FTId=VAR_038604.
FT HELIX 6 15
FT HELIX 18 24
FT TURN 36 38
FT HELIX 41 44
FT TURN 45 48
FT HELIX 50 58
FT HELIX 73 80
FT HELIX 83 91
FT STRAND 101 103
FT HELIX 106 112
FT HELIX 116 125
FT STRAND 135 137
FT HELIX 140 146
FT HELIX 150 158
SQ SEQUENCE 168 AA; 18127 MW; 5D66AFA715186E9A CRC64;
MAEPWGNELA SAAARGDLEQ LTSLLQNNVN VNAQNGFGRT ALQVMKLGNP EIARRLLLRG
ANPDLKDRTG FAVIHDAARA GFLDTLQTLL EFQADVNIED NEGNLPLHLA AKEGHLRVVE
FLVKHTASNV GHRNHKGDTA CDLARLYGRN EVVSLMQANG AGGATNLQ
//
MIM
603369
*RECORD*
*FIELD* NO
603369
*FIELD* TI
*603369 CYCLIN-DEPENDENT KINASE INHIBITOR 2C; CDKN2C
;;p18(INK4C)
*FIELD* TX
DESCRIPTION
read more
Cyclin-dependent kinase inhibitors (CKIs) are a group of low molecular
weight proteins that associate with cyclin-CDK complexes or CDKs alone
and inhibit their activity. Members of the INK4 family of CKIs, which
includes CDKN2C, specifically bind and inhibit CDK4 (123829) and CDK6
(603368), thereby preventing cyclin D-dependent phosphorylation of RB1
(614041). See INK4D (600947).
CLONING
By using a yeast 2-hybrid screen to search for CDK6-interacting
proteins, Guan et al. (1994) isolated a partial cDNA encoding a protein
that they designated p18 based on its molecular mass of 18 kD. They used
the partial cDNA to screen a HeLa cell library and recovered additional
cDNAs corresponding to the entire p18 coding region. Sequence analysis
revealed that the predicted 168-amino acid p18 protein shares 38% and
42% sequence identity with p16/INK4A (600160) and p14/INK4B (600431),
respectively. Like p14 and p16, p18 contains an ankyrin repeat domain.
Using Northern blot analysis, Guan et al. (1994) found that p18 is
expressed as multiple transcripts in various human tissues, with the
strongest expression in skeletal muscle.
GENE FUNCTION
Guan et al. (1994) showed that, both in vivo and in vitro, p18
interacted strongly with CDK6 and weakly with CDK4, but not with the
other CDKs tested. Recombinant p18 inhibited the kinase activity of
cyclin D-CDK6 in vitro. Ectopic expression of either p16 or p18
suppressed the growth of human cells in a manner that appears to
correlate with the presence of a wildtype RB1 function.
GENE STRUCTURE
Blais et al. (1998) determined that the p18, or INK4C, gene contains 3
exons and spans more than 7.5 kb.
MAPPING
By fluorescence in situ hybridization, Guan et al. (1994) mapped the p18
gene to 1p32, a chromosomal region associated with abnormalities in a
variety of human tumors.
MOLECULAR GENETICS
Lapointe et al. (1996) identified a single amino acid substitution
(ala72 to pro; A72P) in BT-20 human breast cancer cells that abrogated
the ability of p18 to interact with CDK6 and to suppress cell growth.
These authors suggested that p18 inactivation by point mutations may
contribute to deregulated growth control in certain cell lines and/or
tumors. Blais et al. (1998) found this p18 variant in 3 of 35 breast
tumors examined, and suggested that it may be a polymorphism.
ANIMAL MODEL
Zindy et al. (2001) determined that both Ink4c and Ink4d were expressed
in the seminiferous tubules of postnatal wildtype mice, being largely
confined to postmitotic spermatocytes undergoing meiosis. Loss of either
Ink4c or Ink4d alone was associated with male fertility, but
double-knockout males were sterile. Spermatogonia did not differentiate
properly and became apoptotic. Residual spermatozoa had reduced motility
and decreased viability. Loss of Ink4c alone or in combination with loss
of Ink4d was associated with impaired differentiation of Leydig cells
and reduced testosterone levels, but there was no effect on the levels
of luteinizing hormone produced by the anterior pituitary. Loss of Ink4c
or Ink4d, either singly or in combination, had no effect on female
reproductive function.
Bai et al. (2003) noted that targeted disruption of Ink4c in mice leads
to spontaneous pituitary tumors and lymphomas later in life. Treatment
of Inc4c null and heterozygous mice with a chemical carcinogen resulted
in tumor development at an accelerated rate. Bai et al. (2003) concluded
that, since the remaining wildtype allele of Ink4c was neither mutated
nor silenced in tumors derived from heterozygotes, Ink4c is a
haploinsufficient tumor suppressor in mice.
Using reconstituted mice with p18-deficient hematopoietic cells and in
vivo evaluation of stem cell function, Yuan et al. (2004) found that p18
inhibited cell division in hematopoietic stem cells and early
hematopoietic progenitor cells.
Nmyc (164840) promotes rapid cell division of granule neuron progenitors
(GNPs) in mice, and its conditional loss during embryonic cerebellar
development results in severe GNP deficiency, perturbs foliation, and
leads to reduced cerebellar mass. Since Nmyc loss triggers precocious
expression of Kip1 (CDKN1B; 600778) and Ink4c in the cerebellar
primordium, Zindy et al. (2006) disrupted Kip1 and Ink4c in Nmyc-null
cerebella and found that this partially rescued GNP cell proliferation
and cerebellar foliation. They concluded that expression of NMYC and
concomitant downregulation of INK4C and KIP1 contribute to the proper
development of the cerebellum.
*FIELD* RF
1. Bai, F.; Pei, X.-H.; Godfrey, V. L.; Xiong, Y.: Haploinsufficiency
of p18(INK4c) sensitizes mice to carcinogen-induced tumorigenesis. Molec.
Cell. Biol. 23: 1269-1277, 2003.
2. Blais, A.; Labrie, Y.; Pouliot, F.; Lachance, Y.; Labrie, C.:
Structure of the gene encoding the human cyclin-dependent kinase inhibitor
p18 and mutational analysis in breast cancer. Biochem. Biophys. Res.
Commun. 247: 146-153, 1998.
3. Guan, K.-L.; Jenkins, C. W.; Li, Y.; Nichols, M. A.; Wu, X.; O'Keefe,
C. L.; Matera, A. G.; Xiong, Y.: Growth suppression by p18, a p16(INK4/MTS1)-
and p14(INK4B/MTS2)-related CDK6 inhibitor, correlates with wild-type
pRb function. Genes Dev. 8: 2939-2952, 1994.
4. Lapointe, J.; Lachance, Y.; Labrie, Y.; Labrie, C.: A p18 mutant
defective in CDK6 binding in human breast cancer cells. Cancer Res. 56:
4586-4589, 1996.
5. Yuan, Y.; Shen, H.; Franklin, D. S.; Scadden, D. T.; Cheng, T.
: In vivo self-renewing divisions of haematopoietic stem cells are
increased in the absence of the early G1-phase inhibitor, p18(INK4C). Nature
Cell Biol. 6: 436-442, 2004.
6. Zindy, F.; den Besten, W.; Chen, B.; Rehg, J. E.; Latres, E.; Barbacid,
M.; Pollard, J. W.; Sherr, C. J.; Cohen, P. E.; Roussel, M. F.: Control
of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors
p18(Ink4c) and p19(Ink4d). Molec. Cell. Biol. 21: 3244-3255, 2001.
7. Zindy, F.; Knoepfler, P. S.; Xie, S.; Sherr, C. J.; Eisenman, R.
N.; Roussel, M. F.: N-Myc and the cyclin-dependent kinase inhibitors
p18(Ink4c) and p27(Kip1) coordinately regulate cerebellar development. Proc.
Nat. Acad. Sci. 103: 11579-11583, 2006.
*FIELD* CN
Patricia A. Hartz - updated: 10/3/2006
Patricia A. Hartz - updated: 5/6/2004
Patricia A. Hartz - updated: 3/27/2003
Patricia A. Hartz - updated: 1/6/2003
*FIELD* CD
Rebekah S. Rasooly: 12/18/1998
*FIELD* ED
alopez: 06/17/2011
mgross: 10/10/2006
terry: 10/3/2006
alopez: 5/28/2004
mgross: 5/6/2004
mgross: 3/27/2003
mgross: 1/8/2003
terry: 1/6/2003
alopez: 12/18/1998
*RECORD*
*FIELD* NO
603369
*FIELD* TI
*603369 CYCLIN-DEPENDENT KINASE INHIBITOR 2C; CDKN2C
;;p18(INK4C)
*FIELD* TX
DESCRIPTION
read more
Cyclin-dependent kinase inhibitors (CKIs) are a group of low molecular
weight proteins that associate with cyclin-CDK complexes or CDKs alone
and inhibit their activity. Members of the INK4 family of CKIs, which
includes CDKN2C, specifically bind and inhibit CDK4 (123829) and CDK6
(603368), thereby preventing cyclin D-dependent phosphorylation of RB1
(614041). See INK4D (600947).
CLONING
By using a yeast 2-hybrid screen to search for CDK6-interacting
proteins, Guan et al. (1994) isolated a partial cDNA encoding a protein
that they designated p18 based on its molecular mass of 18 kD. They used
the partial cDNA to screen a HeLa cell library and recovered additional
cDNAs corresponding to the entire p18 coding region. Sequence analysis
revealed that the predicted 168-amino acid p18 protein shares 38% and
42% sequence identity with p16/INK4A (600160) and p14/INK4B (600431),
respectively. Like p14 and p16, p18 contains an ankyrin repeat domain.
Using Northern blot analysis, Guan et al. (1994) found that p18 is
expressed as multiple transcripts in various human tissues, with the
strongest expression in skeletal muscle.
GENE FUNCTION
Guan et al. (1994) showed that, both in vivo and in vitro, p18
interacted strongly with CDK6 and weakly with CDK4, but not with the
other CDKs tested. Recombinant p18 inhibited the kinase activity of
cyclin D-CDK6 in vitro. Ectopic expression of either p16 or p18
suppressed the growth of human cells in a manner that appears to
correlate with the presence of a wildtype RB1 function.
GENE STRUCTURE
Blais et al. (1998) determined that the p18, or INK4C, gene contains 3
exons and spans more than 7.5 kb.
MAPPING
By fluorescence in situ hybridization, Guan et al. (1994) mapped the p18
gene to 1p32, a chromosomal region associated with abnormalities in a
variety of human tumors.
MOLECULAR GENETICS
Lapointe et al. (1996) identified a single amino acid substitution
(ala72 to pro; A72P) in BT-20 human breast cancer cells that abrogated
the ability of p18 to interact with CDK6 and to suppress cell growth.
These authors suggested that p18 inactivation by point mutations may
contribute to deregulated growth control in certain cell lines and/or
tumors. Blais et al. (1998) found this p18 variant in 3 of 35 breast
tumors examined, and suggested that it may be a polymorphism.
ANIMAL MODEL
Zindy et al. (2001) determined that both Ink4c and Ink4d were expressed
in the seminiferous tubules of postnatal wildtype mice, being largely
confined to postmitotic spermatocytes undergoing meiosis. Loss of either
Ink4c or Ink4d alone was associated with male fertility, but
double-knockout males were sterile. Spermatogonia did not differentiate
properly and became apoptotic. Residual spermatozoa had reduced motility
and decreased viability. Loss of Ink4c alone or in combination with loss
of Ink4d was associated with impaired differentiation of Leydig cells
and reduced testosterone levels, but there was no effect on the levels
of luteinizing hormone produced by the anterior pituitary. Loss of Ink4c
or Ink4d, either singly or in combination, had no effect on female
reproductive function.
Bai et al. (2003) noted that targeted disruption of Ink4c in mice leads
to spontaneous pituitary tumors and lymphomas later in life. Treatment
of Inc4c null and heterozygous mice with a chemical carcinogen resulted
in tumor development at an accelerated rate. Bai et al. (2003) concluded
that, since the remaining wildtype allele of Ink4c was neither mutated
nor silenced in tumors derived from heterozygotes, Ink4c is a
haploinsufficient tumor suppressor in mice.
Using reconstituted mice with p18-deficient hematopoietic cells and in
vivo evaluation of stem cell function, Yuan et al. (2004) found that p18
inhibited cell division in hematopoietic stem cells and early
hematopoietic progenitor cells.
Nmyc (164840) promotes rapid cell division of granule neuron progenitors
(GNPs) in mice, and its conditional loss during embryonic cerebellar
development results in severe GNP deficiency, perturbs foliation, and
leads to reduced cerebellar mass. Since Nmyc loss triggers precocious
expression of Kip1 (CDKN1B; 600778) and Ink4c in the cerebellar
primordium, Zindy et al. (2006) disrupted Kip1 and Ink4c in Nmyc-null
cerebella and found that this partially rescued GNP cell proliferation
and cerebellar foliation. They concluded that expression of NMYC and
concomitant downregulation of INK4C and KIP1 contribute to the proper
development of the cerebellum.
*FIELD* RF
1. Bai, F.; Pei, X.-H.; Godfrey, V. L.; Xiong, Y.: Haploinsufficiency
of p18(INK4c) sensitizes mice to carcinogen-induced tumorigenesis. Molec.
Cell. Biol. 23: 1269-1277, 2003.
2. Blais, A.; Labrie, Y.; Pouliot, F.; Lachance, Y.; Labrie, C.:
Structure of the gene encoding the human cyclin-dependent kinase inhibitor
p18 and mutational analysis in breast cancer. Biochem. Biophys. Res.
Commun. 247: 146-153, 1998.
3. Guan, K.-L.; Jenkins, C. W.; Li, Y.; Nichols, M. A.; Wu, X.; O'Keefe,
C. L.; Matera, A. G.; Xiong, Y.: Growth suppression by p18, a p16(INK4/MTS1)-
and p14(INK4B/MTS2)-related CDK6 inhibitor, correlates with wild-type
pRb function. Genes Dev. 8: 2939-2952, 1994.
4. Lapointe, J.; Lachance, Y.; Labrie, Y.; Labrie, C.: A p18 mutant
defective in CDK6 binding in human breast cancer cells. Cancer Res. 56:
4586-4589, 1996.
5. Yuan, Y.; Shen, H.; Franklin, D. S.; Scadden, D. T.; Cheng, T.
: In vivo self-renewing divisions of haematopoietic stem cells are
increased in the absence of the early G1-phase inhibitor, p18(INK4C). Nature
Cell Biol. 6: 436-442, 2004.
6. Zindy, F.; den Besten, W.; Chen, B.; Rehg, J. E.; Latres, E.; Barbacid,
M.; Pollard, J. W.; Sherr, C. J.; Cohen, P. E.; Roussel, M. F.: Control
of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors
p18(Ink4c) and p19(Ink4d). Molec. Cell. Biol. 21: 3244-3255, 2001.
7. Zindy, F.; Knoepfler, P. S.; Xie, S.; Sherr, C. J.; Eisenman, R.
N.; Roussel, M. F.: N-Myc and the cyclin-dependent kinase inhibitors
p18(Ink4c) and p27(Kip1) coordinately regulate cerebellar development. Proc.
Nat. Acad. Sci. 103: 11579-11583, 2006.
*FIELD* CN
Patricia A. Hartz - updated: 10/3/2006
Patricia A. Hartz - updated: 5/6/2004
Patricia A. Hartz - updated: 3/27/2003
Patricia A. Hartz - updated: 1/6/2003
*FIELD* CD
Rebekah S. Rasooly: 12/18/1998
*FIELD* ED
alopez: 06/17/2011
mgross: 10/10/2006
terry: 10/3/2006
alopez: 5/28/2004
mgross: 5/6/2004
mgross: 3/27/2003
mgross: 1/8/2003
terry: 1/6/2003
alopez: 12/18/1998