P25322 (CCND1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
G1/S-specific cyclin-D1

Gene names

Name:	Ccnd1
Synonyms:	Cyl-1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	295 AA.
Sequence status	Complete.
Protein existence	Evidence 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 By similarity.
Subunit structure	Interacts with USP2. Interacts with UHRF2; the interaction ubiquitinates CCND1 and appears independently of phosphorylation 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 process	Cell cycle Cell division
Cellular component	Cytoplasm Membrane Nucleus
Molecular function	Cyclin
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1/S transition of mitotic cell cycle Inferred from sequence or structural similarity. Source: UniProtKB Leydig cell differentiation Inferred from electronic annotation. Source: Compara canonical Wnt receptor signaling pathway Inferred from mutant phenotype PubMed 15314168. Source: MGI cell division Inferred from electronic annotation. Source: UniProtKB-KW 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: Compara 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 receptor signaling pathway Inferred from mutant phenotype PubMed 15314168. Source: MGI negative regulation of epithelial cell differentiation Inferred from genetic interaction PubMed 15314168. Source: MGI organ regeneration Inferred from electronic annotation. Source: Compara 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 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 response to UV-A Inferred from sequence or structural similarity. Source: UniProtKB response to X-ray Inferred from electronic annotation. Source: Compara response to calcium ion Inferred from electronic annotation. Source: Compara response to corticosterone stimulus Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to estrogen stimulus Inferred from electronic annotation. Source: Compara response to ethanol Inferred from electronic annotation. Source: Compara response to iron ion Inferred from electronic annotation. Source: Compara response to magnesium ion Inferred from electronic annotation. Source: Compara response to organic nitrogen Inferred from electronic annotation. Source: Compara response to vitamin E Inferred from electronic annotation. Source: Compara
Cellular_component	cyclin-dependent protein kinase holoenzyme complex Inferred from physical interaction Ref.6. Source: UniProtKB cytosol Traceable author statement. Source: Reactome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	cyclin-dependent protein serine/threonine kinase regulator activity Inferred from direct assay PubMed 12502791. Source: MGI protein kinase activity Inferred from direct assay PubMed 12588994. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Cdk4	P30285	9	EBI-847243,EBI-847225
Prmt5	Q8CIG8	5	EBI-847243,EBI-2527009

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 295	295	G1/S-specific cyclin-D1		PRO_0000080431
Regions
	Domain	28 – 152	125	Cyclin N-terminal
	Compositional bias	273 – 280	8	Glu-rich
Amino acid modifications
	Modified residue	286	1	Phosphothreonine Ref.5
	Cross-link	269		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.6
Experimental info
	Mutagenesis	269	1	K → R: Promotes location to the nucleus. Reduces proteasomal degradation, but does not prevent ubiquitination. Ref.6
	Mutagenesis	286	1	T → A: Constitutively nuclear. Strongly reduced interaction with FBXO4. Strongly reduced ubiquitination. Ref.5 Ref.6

Sequences

	Sequence		Length	Mass (Da)
	P25322 [UniParc]. Last modified May 1, 1992. Version 1. Checksum: 3A79736B4163251B	FASTA	295	33,429
	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

References

	« Hide 'large scale' referencesShow '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.
IPI	IPI00109561.
PIR	A56523.
RefSeq	NP_031657.1. NM_007631.2.
UniGene	Mm.273049.
3D structure databases
ProteinModelPortal	P25322.
SMR	P25322. Positions 22-267.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-284N.
IntAct	P25322. 16 interactions.
MINT	MINT-1510765.
PTM databases
PhosphoSite	P25322.
Proteomic databases
PaxDb	P25322.
PRIDE	P25322.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000093962; ENSMUSP00000091495; ENSMUSG00000070348.
GeneID	12443.
KEGG	mmu:12443.
Organism-specific databases
CTD	595.
MGI	MGI:88313. Ccnd1.
Phylogenomic databases
eggNOG	COG5024.
HOGENOM	HOG000008182.
HOVERGEN	HBG050837.
InParanoid	P25322.
KO	K04503.
OMA	MKETVPL.
OrthoDB	EOG4JWVF1.
Enzyme and pathway databases
Reactome	REACT_118161. Cell Cycle.
Gene expression databases
ArrayExpress	P25322.
Bgee	P25322.
CleanEx	MM_CCND1.
Genevestigator	P25322.
GermOnline	ENSMUSG00000070348. Mus musculus.
Family and domain databases
Gene3D	1.10.472.10. 2 hits.
InterPro	IPR013763. Cyclin-like. IPR014400. Cyclin_A/B/D/E. IPR004367. Cyclin_C-dom. IPR006671. Cyclin_N. [Graphical view]
Pfam	PF02984. Cyclin_C. 1 hit. PF00134. Cyclin_N. 1 hit. [Graphical view]
PIRSF	PIRSF001771. Cyclin_A_B_D_E. 1 hit.
SMART	SM00385. CYCLIN. 2 hits. [Graphical view]
SUPFAM	SSF47954. Cyclin_like. 2 hits.
PROSITE	PS00292. CYCLINS. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P25322.
NextBio	281254.
SOURCE	Search...

Entry information

Entry name

CCND1_MOUSE

Accession

Primary (citable) accession number: P25322

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1992
Last sequence update:	May 1, 1992
Last modified:	May 1, 2013
This is version 122 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program