CCND1_MOUSE
ID CCND1_MOUSE Reviewed; 295 AA.
AC P25322;
DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1992, sequence version 1.
DT 03-AUG-2022, entry version 197.
DE RecName: Full=G1/S-specific cyclin-D1;
GN Name=Ccnd1; Synonyms=Cyl-1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1827757; DOI=10.1016/0092-8674(91)90101-4;
RA Matsushime H., Roussel M.F., Ashmun R.A., Sherr C.J.;
RT "Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of
RT the cell cycle.";
RL Cell 65:701-713(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7774959; DOI=10.1016/0888-7543(95)80112-y;
RA Smith R., Peters G., Dickson C.;
RT "Genomic organization of the mouse cyclin D1 gene (Cyl-1).";
RL Genomics 25:85-92(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=129; TISSUE=Mammary gland;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH CDKN1B IN THE CCND1-CDK4-CDKN1B COMPLEX.
RX PubMed=8534916; DOI=10.1091/mbc.6.9.1197;
RA Poon R.Y., Toyoshima H., Hunter T.;
RT "Redistribution of the CDK inhibitor p27 between different cyclin.CDK
RT complexes in the mouse fibroblast cell cycle and in cells arrested with
RT lovastatin or ultraviolet irradiation.";
RL Mol. Biol. Cell 6:1197-1213(1995).
RN [5]
RP UBIQUITINATION, INTERACTION WITH FBXO4, INTERACTION WITH A UBIQUITIN LIGASE
RP COMPLEX CONTAINING CRYAB, SKP1, CUL1 AND FBXO4, MUTAGENESIS OF THR-286, AND
RP PHOSPHORYLATION AT THR-286.
RX PubMed=17081987; DOI=10.1016/j.molcel.2006.09.007;
RA Lin D.I., Barbash O., Kumar K.G., Weber J.D., Harper J.W.,
RA Klein-Szanto A.J., Rustgi A., Fuchs S.Y., Diehl J.A.;
RT "Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-
RT alphaB crystallin) complex.";
RL Mol. Cell 24:355-366(2006).
RN [6]
RP UBIQUITINATION AT LYS-269, INTERACTION WITH CDKN1B AND CDK4, SUBUNIT,
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-269 AND THR-286.
RX PubMed=19767775; DOI=10.1038/onc.2009.287;
RA Barbash O., Egan E., Pontano L.L., Kosak J., Diehl J.A.;
RT "Lysine 269 is essential for cyclin D1 ubiquitylation by the
RT SCF(Fbx4/alphaB-crystallin) ligase and subsequent proteasome-dependent
RT degradation.";
RL Oncogene 28:4317-4325(2009).
RN [7]
RP UBIQUITINATION.
RX PubMed=33854232; DOI=10.1038/s41586-021-03422-5;
RA Maiani E., Milletti G., Nazio F., Holdgaard S.G., Bartkova J., Rizza S.,
RA Cianfanelli V., Lorente M., Simoneschi D., Di Marco M., D'Acunzo P.,
RA Di Leo L., Rasmussen R., Montagna C., Raciti M., De Stefanis C.,
RA Gabicagogeascoa E., Rona G., Salvador N., Pupo E., Merchut-Maya J.M.,
RA Daniel C.J., Carinci M., Cesarini V., O'sullivan A., Jeong Y.T., Bordi M.,
RA Russo F., Campello S., Gallo A., Filomeni G., Lanzetti L., Sears R.C.,
RA Hamerlik P., Bartolazzi A., Hynds R.E., Pearce D.R., Swanton C., Pagano M.,
RA Velasco G., Papaleo E., De Zio D., Maya-Mendoza A., Locatelli F.,
RA Bartek J., Cecconi F.;
RT "AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity.";
RL Nature 592:799-803(2021).
CC -!- FUNCTION: Regulatory component of the cyclin D1-CDK4 (DC) complex that
CC phosphorylates and inhibits members of the retinoblastoma (RB) protein
CC family including RB1 and regulates the cell-cycle during G(1)/S
CC transition. Phosphorylation of RB1 allows dissociation of the
CC transcription factor E2F from the RB/E2F complex and the subsequent
CC transcription of E2F target genes which are responsible for the
CC progression through the G(1) phase. Hypophosphorylates RB1 in early
CC G(1) phase. Cyclin D-CDK4 complexes are major integrators of various
CC mitogenenic and antimitogenic signals. Also a substrate for SMAD3,
CC phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing
CC its transcriptional activity. Component of the ternary complex, cyclin
CC D1/CDK4/CDKN1B, required for nuclear translocation and activity of the
CC cyclin D-CDK4 complex. Exhibits transcriptional corepressor activity
CC with INSM1 on the NEUROD1 and INS promoters in a cell cycle-independent
CC manner. {ECO:0000250|UniProtKB:P24385}.
CC -!- SUBUNIT: Interacts with either CDK4 or CDK6 protein kinase to form a
CC serine/threonine kinase holoenzyme complex. The cyclin subunit imparts
CC substrate specificity to the complex. Component of the ternary complex
CC CCND1/CDK4/CDKN1B required for nuclear translocation and modulation of
CC CDK4-mediated kinase activity (By similarity). Interacts directly with
CC CDKN1B (PubMed:8534916, PubMed:19767775). Can form similar complexes
CC with either CDKN1A or CDKN2A (PubMed:8534916). Interacts with FBXO4
CC (PubMed:17081987). Interacts with UHRF2; the interaction ubiquitinates
CC CCND1 and appears to occur independently of phosphorylation. Interacts
CC with USP2. Interacts (via cyclin N-terminal domain) with INSM1 (via N-
CC terminal region); the interaction competes with the binding of CCND1 to
CC CDK4 during cell cycle progression and inhibits CDK4 activity.
CC Interacts with CDK4; the interaction is prevented with the binding of
CC CCND1 to INSM1 during cell cycle progression (By similarity).
CC {ECO:0000250|UniProtKB:P24385, ECO:0000269|PubMed:17081987,
CC ECO:0000269|PubMed:19767775, ECO:0000269|PubMed:8534916}.
CC -!- INTERACTION:
CC P25322; P30285: Cdk4; NbExp=15; IntAct=EBI-847243, EBI-847225;
CC P25322; Q8CIG8: Prmt5; NbExp=5; IntAct=EBI-847243, EBI-2527009;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:19767775}. Cytoplasm
CC {ECO:0000250|UniProtKB:P24385}. Nucleus membrane
CC {ECO:0000250|UniProtKB:P24385}. Note=Cyclin D-CDK4 complexes accumulate
CC at the nuclear membrane and are then translocated into the nucleus
CC through interaction with KIP/CIP family members.
CC {ECO:0000250|UniProtKB:P24385}.
CC -!- PTM: Phosphorylation at Thr-286 by MAP kinases is required for
CC ubiquitination and degradation by the DCX(AMBRA1) complex (By
CC similarity). It also plays an essential role for recognition by the
CC FBXO31 component of SCF (SKP1-cullin-F-box) protein ligase complex
CC following DNA damage (By similarity). {ECO:0000250|UniProtKB:P24385}.
CC -!- PTM: Ubiquitinated at Lys-269 by the DCX(AMBRA1) complex during the
CC transition from G1 to S cell phase, leading to its degradation:
CC ubiquitination is dependent on Thr-286 phosphorylation
CC (PubMed:33854232). The DCX(AMBRA1) complex represents the major
CC regulator of CCND1 stability during the G1/S transition
CC (PubMed:33854232). Also ubiquitinated by a SCF (SKP1-CUL1-F-box
CC protein) ubiquitin-protein ligase complex containing FBXO4 and CRYAB
CC (PubMed:17081987, PubMed:19767775). Following DNA damage it is
CC ubiquitinated by some SCF (SKP1-cullin-F-box) protein ligase complex
CC containing FBXO31. SCF-type ubiquitination is dependent on Thr-286
CC phosphorylation. Ubiquitinated also by UHRF2 apparently in a
CC phosphorylation-independent manner. Ubiquitination leads to its
CC degradation and G1 arrest. Deubiquitinated by USP2; leading to its
CC stabilization (By similarity). {ECO:0000250|UniProtKB:P24385,
CC ECO:0000269|PubMed:17081987, ECO:0000269|PubMed:19767775,
CC ECO:0000269|PubMed:33854232}.
CC -!- SIMILARITY: Belongs to the cyclin family. Cyclin D subfamily.
CC {ECO:0000305}.
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DR EMBL; M64403; AAA37502.1; -; mRNA.
DR EMBL; S78355; AAB34495.1; -; mRNA.
DR EMBL; BC044841; AAH44841.1; -; mRNA.
DR CCDS; CCDS22055.1; -.
DR PIR; A56523; A56523.
DR RefSeq; NP_031657.1; NM_007631.2.
DR AlphaFoldDB; P25322; -.
DR SMR; P25322; -.
DR BioGRID; 198548; 17.
DR ComplexPortal; CPX-2073; Cyclin D1-CDK4 complex.
DR ComplexPortal; CPX-2080; Cyclin D1-CDK6 complex.
DR CORUM; P25322; -.
DR DIP; DIP-284N; -.
DR ELM; P25322; -.
DR IntAct; P25322; 22.
DR MINT; P25322; -.
DR STRING; 10090.ENSMUSP00000091495; -.
DR BindingDB; P25322; -.
DR iPTMnet; P25322; -.
DR PhosphoSitePlus; P25322; -.
DR PaxDb; P25322; -.
DR PeptideAtlas; P25322; -.
DR PRIDE; P25322; -.
DR ProteomicsDB; 281250; -.
DR Antibodypedia; 3660; 2089 antibodies from 53 providers.
DR DNASU; 12443; -.
DR Ensembl; ENSMUST00000093962; ENSMUSP00000091495; ENSMUSG00000070348.
DR GeneID; 12443; -.
DR KEGG; mmu:12443; -.
DR UCSC; uc009kqt.1; mouse.
DR CTD; 595; -.
DR MGI; MGI:88313; Ccnd1.
DR VEuPathDB; HostDB:ENSMUSG00000070348; -.
DR eggNOG; KOG0656; Eukaryota.
DR GeneTree; ENSGT00940000157816; -.
DR HOGENOM; CLU_052190_0_0_1; -.
DR InParanoid; P25322; -.
DR OMA; SCYRTTH; -.
DR OrthoDB; 1234739at2759; -.
DR PhylomeDB; P25322; -.
DR TreeFam; TF101004; -.
DR Reactome; R-MMU-187577; SCF(Skp2)-mediated degradation of p27/p21.
DR Reactome; R-MMU-3214858; RMTs methylate histone arginines.
DR Reactome; R-MMU-69231; Cyclin D associated events in G1.
DR Reactome; R-MMU-75815; Ubiquitin-dependent degradation of Cyclin D.
DR Reactome; R-MMU-8849470; PTK6 Regulates Cell Cycle.
DR Reactome; R-MMU-8878166; Transcriptional regulation by RUNX2.
DR Reactome; R-MMU-8934593; Regulation of RUNX1 Expression and Activity.
DR Reactome; R-MMU-8951936; RUNX3 regulates p14-ARF.
DR Reactome; R-MMU-9754119; Drug-mediated inhibition of CDK4/CDK6 activity.
DR BioGRID-ORCS; 12443; 9 hits in 72 CRISPR screens.
DR ChiTaRS; Ccnd1; mouse.
DR PRO; PR:P25322; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; P25322; protein.
DR Bgee; ENSMUSG00000070348; Expressed in vault of skull and 314 other tissues.
DR ExpressionAtlas; P25322; baseline and differential.
DR Genevisible; P25322; MM.
DR GO; GO:0005923; C:bicellular tight junction; IDA:MGI.
DR GO; GO:0097128; C:cyclin D1-CDK4 complex; IPI:ComplexPortal.
DR GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IPI:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0017053; C:transcription repressor complex; ISS:UniProtKB.
DR GO; GO:0016538; F:cyclin-dependent protein serine/threonine kinase regulator activity; IDA:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0042826; F:histone deacetylase binding; ISO:MGI.
DR GO; GO:0016301; F:kinase activity; IDA:MGI.
DR GO; GO:0070064; F:proline-rich region binding; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0003714; F:transcription corepressor activity; ISS:UniProtKB.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0008283; P:cell population proliferation; IMP:MGI.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0071310; P:cellular response to organic substance; IDA:MGI.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IDA:MGI.
DR GO; GO:0045444; P:fat cell differentiation; IDA:MGI.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IDA:MGI.
DR GO; GO:0007595; P:lactation; IMP:MGI.
DR GO; GO:0033327; P:Leydig cell differentiation; ISO:MGI.
DR GO; GO:0097421; P:liver regeneration; IDA:MGI.
DR GO; GO:0060749; P:mammary gland alveolus development; IMP:MGI.
DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; IGI:MGI.
DR GO; GO:0044772; P:mitotic cell cycle phase transition; IBA:GO_Central.
DR GO; GO:0031571; P:mitotic G1 DNA damage checkpoint signaling; ISS:UniProtKB.
DR GO; GO:0030857; P:negative regulation of epithelial cell differentiation; IGI:MGI.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IGI:MGI.
DR GO; GO:0030182; P:neuron differentiation; IMP:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0045737; P:positive regulation of cyclin-dependent protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:1900087; P:positive regulation of G1/S transition of mitotic cell cycle; IBA:GO_Central.
DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:0033601; P:positive regulation of mammary gland epithelial cell proliferation; IGI:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:0000320; P:re-entry into mitotic cell cycle; IDA:MGI.
DR GO; GO:0051726; P:regulation of cell cycle; IDA:MGI.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IGI:MGI.
DR GO; GO:0051592; P:response to calcium ion; IEA:Ensembl.
DR GO; GO:0051412; P:response to corticosterone; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR GO; GO:0043627; P:response to estrogen; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0010039; P:response to iron ion; IEA:Ensembl.
DR GO; GO:0044321; P:response to leptin; ISO:MGI.
DR GO; GO:0032026; P:response to magnesium ion; IEA:Ensembl.
DR GO; GO:0010243; P:response to organonitrogen compound; ISO:MGI.
DR GO; GO:0070141; P:response to UV-A; ISS:UniProtKB.
DR GO; GO:0033197; P:response to vitamin E; IEA:Ensembl.
DR GO; GO:0010165; P:response to X-ray; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0016055; P:Wnt signaling pathway; IDA:MGI.
DR CDD; cd00043; CYCLIN; 1.
DR InterPro; IPR039361; Cyclin.
DR InterPro; IPR013763; Cyclin-like.
DR InterPro; IPR036915; Cyclin-like_sf.
DR InterPro; IPR004367; Cyclin_C-dom.
DR InterPro; IPR015451; Cyclin_D.
DR InterPro; IPR006671; Cyclin_N.
DR PANTHER; PTHR10177; PTHR10177; 1.
DR PANTHER; PTHR10177:SF67; PTHR10177:SF67; 1.
DR Pfam; PF02984; Cyclin_C; 1.
DR Pfam; PF00134; Cyclin_N; 1.
DR SMART; SM00385; CYCLIN; 2.
DR SMART; SM01332; Cyclin_C; 1.
DR SUPFAM; SSF47954; SSF47954; 2.
DR PROSITE; PS00292; CYCLINS; 1.
PE 1: Evidence at protein level;
KW Cell cycle; Cell division; Cyclin; Cytoplasm; Isopeptide bond; Membrane;
KW Nucleus; Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..295
FT /note="G1/S-specific cyclin-D1"
FT /id="PRO_0000080431"
FT DOMAIN 28..152
FT /note="Cyclin N-terminal"
FT REGION 262..283
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 286
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:17081987"
FT CROSSLNK 269
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:19767775"
FT MUTAGEN 269
FT /note="K->R: Promotes location to the nucleus. Reduces
FT proteasomal degradation, but does not prevent
FT ubiquitination."
FT /evidence="ECO:0000269|PubMed:19767775"
FT MUTAGEN 286
FT /note="T->A: Constitutively nuclear. Strongly reduced
FT interaction with FBXO4. Strongly reduced ubiquitination."
FT /evidence="ECO:0000269|PubMed:17081987,
FT ECO:0000269|PubMed:19767775"
SQ SEQUENCE 295 AA; 33429 MW; 3A79736B4163251B CRC64;
MEHQLLCCEV ETIRRAYPDT NLLNDRVLRA MLKTEETCAP SVSYFKCVQK EIVPSMRKIV
ATWMLEVCEE QKCEEEVFPL AMNYLDRFLS LEPLKKSRLQ LLGATCMFVA SKMKETIPLT
AEKLCIYTDN SIRPEELLQM ELLLVNKLKW NLAAMTPHDF IEHFLSKMPE ADENKQTIRK
HAQTFVALCA TDVKFISNPP SMVAAGSVVA AMQGLNLGSP NNFLSCYRTT HFLSRVIKCD
PDCLRACQEQ IEALLESSLR QAQQNVDPKA TEEEGEVEEE AGLACTPTDV RDVDI
