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P25322 (CCND1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 132. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
G1/S-specific cyclin-D1
Gene names
Name:Ccnd1
Synonyms:Cyl-1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length295 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. Hypophosphorylates RB1 in early G1 phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity. Component of the ternary complex, cyclin D1/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. Exhibits transcriptional corepressor activity with INSM1 on the NEUROD1 and INS promoters in a cell cycle-independent manner By similarity.

Subunit structure

Interacts with USP2. Interacts with UHRF2; the interaction ubiquitinates CCND1 and appears independently of phosphorylation. Interacts (via cyclin N-terminus domain) with INSM1 (via N-terminus region); the interaction competes with the binding of CCND1 to CDK4 during cell cycle progression and inhibits CDK4 activity. Interacts with CDK4; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression By similarity. Interacts with either CDK4 or CDK6 protein kinase to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex. Component of the ternary complex cyclin D/CDK4/CDKN1B required for nuclear translocation and modulation of CDK4-mediated kinase activity. Interacts directly with CDKN1B. Can form similar complexes with either CDKN1A or CDKN2A. Interacts with FBXO4. Ref.4 Ref.5 Ref.6

Subcellular location

Nucleus. Cytoplasm By similarity. Membrane By similarity. Note: Cyclin D-CDK4 complexes accumulate at the nuclear membrane and are then translocated into the nucleus through interaction with KIP/CIP family members. Ref.6

Post-translational modification

Phosphorylation at Thr-286 by MAP kinases is required for ubiquitination and degradation following DNA damage. It probably plays an essential role for recognition by the FBXO31 component of SCF (SKP1-cullin-F-box) protein ligase complex By similarity.

Ubiquitinated, primarily as 'Lys-48'-linked polyubiquitination. Ubiquitinated by a SCF (SKP1-CUL1-F-box protein) ubiquitin-protein ligase complex containing FBXO4 and CRYAB. Following DNA damage it is ubiquitinated by some SCF (SKP1-cullin-F-box) protein ligase complex containing FBXO31. SCF-type ubiquitination is dependent on Thr-286 phosphorylation. Ubiquitinated also by UHRF2 apparently in a phosphorylation-independent manner By similarity. Ubiquitination leads to its degradation and G1 arrest. Deubiquitinated by USP2; leading to its stabilization. Ref.5 Ref.6

Sequence similarities

Belongs to the cyclin family. Cyclin D subfamily.

Contains 1 cyclin N-terminal domain.

Ontologies

Keywords
   Biological processCell cycle
Cell division
Transcription
Transcription regulation
   Cellular componentCytoplasm
Membrane
Nucleus
   Molecular functionCyclin
Repressor
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG1/S transition of mitotic cell cycle

Inferred from sequence or structural similarity. Source: UniProtKB

Leydig cell differentiation

Inferred from electronic annotation. Source: Ensembl

Wnt signaling pathway

Inferred from direct assay PubMed 19056892. Source: MGI

canonical Wnt signaling pathway

Inferred from mutant phenotype PubMed 15314168. Source: MGI

cell division

Inferred from electronic annotation. Source: UniProtKB-KW

cellular response to DNA damage stimulus

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to organic substance

Inferred from direct assay PubMed 18604197. Source: MGI

endoplasmic reticulum unfolded protein response

Inferred from direct assay PubMed 16176978. Source: MGI

fat cell differentiation

Inferred from direct assay PubMed 12502791. Source: MGI

lactation

Inferred from mutant phenotype PubMed 10419681. Source: MGI

liver development

Inferred from electronic annotation. Source: Ensembl

mammary gland alveolus development

Inferred from mutant phenotype PubMed 10419681. Source: MGI

mammary gland epithelial cell proliferation

Inferred from genetic interaction PubMed 11747812. Source: MGI

mitotic G1 DNA damage checkpoint

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of Wnt signaling pathway

Inferred from mutant phenotype PubMed 15314168. Source: MGI

negative regulation of cell cycle arrest

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of epithelial cell differentiation

Inferred from genetic interaction PubMed 15314168. Source: MGI

negative regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: UniProtKB

organ regeneration

Inferred from electronic annotation. Source: Ensembl

positive regulation of G2/M transition of mitotic cell cycle

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cyclin-dependent protein kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of mammary gland epithelial cell proliferation

Inferred from genetic interaction PubMed 20075866. Source: MGI

positive regulation of protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

protein phosphorylation

Inferred from direct assay PubMed 12124778PubMed 12588994. Source: MGI

re-entry into mitotic cell cycle

Inferred from direct assay PubMed 12502791. Source: MGI

regulation of G1/S transition of mitotic cell cycle

Inferred from genetic interaction PubMed 21411630. Source: MGI

regulation of cell cycle

Inferred from direct assay PubMed 11809706PubMed 12588994. Source: MGI

response to UV-A

Inferred from sequence or structural similarity. Source: UniProtKB

response to X-ray

Inferred from electronic annotation. Source: Ensembl

response to calcium ion

Inferred from electronic annotation. Source: Ensembl

response to corticosterone

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

response to estrogen

Inferred from electronic annotation. Source: Ensembl

response to ethanol

Inferred from electronic annotation. Source: Ensembl

response to iron ion

Inferred from electronic annotation. Source: Ensembl

response to magnesium ion

Inferred from electronic annotation. Source: Ensembl

response to organonitrogen compound

Inferred from electronic annotation. Source: Ensembl

response to vitamin E

Inferred from electronic annotation. Source: Ensembl

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcyclin-dependent protein kinase holoenzyme complex

Inferred from physical interaction Ref.6. Source: UniProtKB

cytoplasm

Inferred from direct assay PubMed 19531352. Source: MGI

cytosol

Traceable author statement. Source: Reactome

membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay Ref.6. Source: UniProtKB

transcriptional repressor complex

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functioncyclin-dependent protein serine/threonine kinase regulator activity

Inferred from direct assay PubMed 12502791. Source: MGI

kinase activity

Inferred from direct assay PubMed 12124778. Source: MGI

protein kinase activity

Inferred from direct assay PubMed 12588994. Source: MGI

protein kinase binding

Inferred from physical interaction Ref.6. Source: UniProtKB

transcription corepressor activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Cdk4P3028513EBI-847243,EBI-847225
Prmt5Q8CIG85EBI-847243,EBI-2527009

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 295295G1/S-specific cyclin-D1
PRO_0000080431

Regions

Domain28 – 152125Cyclin N-terminal
Compositional bias273 – 2808Glu-rich

Amino acid modifications

Modified residue2861Phosphothreonine Ref.5
Cross-link269Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.6

Experimental info

Mutagenesis2691K → R: Promotes location to the nucleus. Reduces proteasomal degradation, but does not prevent ubiquitination. Ref.6
Mutagenesis2861T → A: Constitutively nuclear. Strongly reduced interaction with FBXO4. Strongly reduced ubiquitination. Ref.5 Ref.6

Sequences

Sequence LengthMass (Da)Tools
P25322 [UniParc].

Last modified May 1, 1992. Version 1.
Checksum: 3A79736B4163251B

FASTA29533,429
        10         20         30         40         50         60 
MEHQLLCCEV ETIRRAYPDT NLLNDRVLRA MLKTEETCAP SVSYFKCVQK EIVPSMRKIV 

        70         80         90        100        110        120 
ATWMLEVCEE QKCEEEVFPL AMNYLDRFLS LEPLKKSRLQ LLGATCMFVA SKMKETIPLT 

       130        140        150        160        170        180 
AEKLCIYTDN SIRPEELLQM ELLLVNKLKW NLAAMTPHDF IEHFLSKMPE ADENKQTIRK 

       190        200        210        220        230        240 
HAQTFVALCA TDVKFISNPP SMVAAGSVVA AMQGLNLGSP NNFLSCYRTT HFLSRVIKCD 

       250        260        270        280        290 
PDCLRACQEQ IEALLESSLR QAQQNVDPKA TEEEGEVEEE AGLACTPTDV RDVDI 

« Hide

References

« Hide 'large scale' references
[1]"Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle."
Matsushime H., Roussel M.F., Ashmun R.A., Sherr C.J.
Cell 65:701-713(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Genomic organization of the mouse cyclin D1 gene (Cyl-1)."
Smith R., Peters G., Dickson C.
Genomics 25:85-92(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: 129.
Tissue: Mammary gland.
[4]"Redistribution of the CDK inhibitor p27 between different cyclin.CDK complexes in the mouse fibroblast cell cycle and in cells arrested with lovastatin or ultraviolet irradiation."
Poon R.Y., Toyoshima H., Hunter T.
Mol. Biol. Cell 6:1197-1213(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CDKN1B IN THE CCND1-CDK4-CDKN1B COMPLEX.
[5]"Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex."
Lin D.I., Barbash O., Kumar K.G., Weber J.D., Harper J.W., Klein-Szanto A.J., Rustgi A., Fuchs S.Y., Diehl J.A.
Mol. Cell 24:355-366(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, INTERACTION WITH FBXO4, INTERACTION WITH A UBIQUITIN LIGASE COMPLEX CONTAINING CRYAB, SKP1, CUL1 AND FBXO4, MUTAGENESIS OF THR-286, PHOSPHORYLATION AT THR-286.
[6]"Lysine 269 is essential for cyclin D1 ubiquitylation by the SCF(Fbx4/alphaB-crystallin) ligase and subsequent proteasome-dependent degradation."
Barbash O., Egan E., Pontano L.L., Kosak J., Diehl J.A.
Oncogene 28:4317-4325(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION AT LYS-269, INTERACTION WITH CDKN1B AND CDK4, SUBUNIT, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-269 AND THR-286.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M64403 mRNA. Translation: AAA37502.1.
S78355 mRNA. Translation: AAB34495.1.
BC044841 mRNA. Translation: AAH44841.1.
PIRA56523.
RefSeqNP_031657.1. NM_007631.2.
UniGeneMm.273049.

3D structure databases

ProteinModelPortalP25322.
SMRP25322. Positions 22-267.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198548. 16 interactions.
DIPDIP-284N.
IntActP25322. 16 interactions.
MINTMINT-1510765.

Chemistry

BindingDBP25322.

PTM databases

PhosphoSiteP25322.

Proteomic databases

PaxDbP25322.
PRIDEP25322.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000093962; ENSMUSP00000091495; ENSMUSG00000070348.
GeneID12443.
KEGGmmu:12443.
UCSCuc009kqt.1. mouse.

Organism-specific databases

CTD595.
MGIMGI:88313. Ccnd1.

Phylogenomic databases

eggNOGCOG5024.
HOGENOMHOG000008182.
HOVERGENHBG050837.
InParanoidP25322.
KOK04503.
OMAMKETVPL.
OrthoDBEOG7J447H.
PhylomeDBP25322.
TreeFamTF101004.

Enzyme and pathway databases

ReactomeREACT_188257. Signal Transduction.
REACT_188804. Cell Cycle.

Gene expression databases

ArrayExpressP25322.
BgeeP25322.
CleanExMM_CCND1.
GenevestigatorP25322.

Family and domain databases

Gene3D1.10.472.10. 2 hits.
InterProIPR013763. Cyclin-like.
IPR014400. Cyclin_A/B/D/E.
IPR004367. Cyclin_C-dom.
IPR015451. Cyclin_D.
IPR006671. Cyclin_N.
[Graphical view]
PANTHERPTHR10177:SF67. PTHR10177:SF67. 1 hit.
PfamPF02984. Cyclin_C. 1 hit.
PF00134. Cyclin_N. 1 hit.
[Graphical view]
PIRSFPIRSF001771. Cyclin_A_B_D_E. 1 hit.
SMARTSM00385. CYCLIN. 2 hits.
[Graphical view]
SUPFAMSSF47954. SSF47954. 2 hits.
PROSITEPS00292. CYCLINS. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio281254.
PROP25322.
SOURCESearch...

Entry information

Entry nameCCND1_MOUSE
AccessionPrimary (citable) accession number: P25322
Entry history
Integrated into UniProtKB/Swiss-Prot: May 1, 1992
Last sequence update: May 1, 1992
Last modified: April 16, 2014
This is version 132 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot