P24385 (CCND1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
G1/S-specific cyclin-D1

Alternative name(s):
B-cell lymphoma 1 protein
Short name=BCL-1
BCL-1 oncogene
PRAD1 oncogene

Gene names

Name:	CCND1
Synonyms:	BCL1, PRAD1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

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. Ref.12 Ref.14
Subunit structure	Interacts with FBXO4 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 CCND1/CDK4/CDKN1B required for nuclear translocation and modulation of CDK4-mediated kinase activity. Interacts directly with CDKN1B. Interacts with UHRF2; the interaction ubiquitinates CCND1 and appears to occur independently of phosphorylation. Can form similar complexes with either CDKN1A or CDKN2A. Interacts with USP2. Ref.10 Ref.12 Ref.15 Ref.17
Subcellular location	Nucleus. Cytoplasm. Membrane. Note: Cyclin D-CDK4 complexes accumulate at the nuclear membrane and are then translocated to the nucleus through interaction with KIP/CIP family members By similarity. Ref.12
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. 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 By similarity. Ubiquitinated also by UHRF2 apparently in a phosphorylation-independent manner. Ubiquitination leads to its degradation and G1 arrest. Deubiquitinated by USP2; leading to its stabilization. Ref.13 Ref.15 Ref.16 Ref.17
Involvement in disease	A chromosomal aberration involving CCND1 may be a cause of B-lymphocytic malignancy, particularly mantle-cell lymphoma (MCL). Translocation t(11;14)(q13;q32) with immunoglobulin gene regions. Activation of CCND1 may be oncogenic by directly altering progression through the cell cycle. A chromosomal aberration involving CCND1 may be a cause of parathyroid adenomas. Translocation t(11;11)(q13;p15) with the parathyroid hormone (PTH) enhancer. Multiple myeloma (MM) [MIM:254500]: A malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note: The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving CCND1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus.
Sequence similarities	Belongs to the cyclin family. Cyclin D subfamily. Contains 1 cyclin N-terminal domain.

Ontologies

Keywords
Biological process	Cell cycle Cell division DNA damage
Cellular component	Cytoplasm Membrane Nucleus
Coding sequence diversity	Chromosomal rearrangement
Disease	Proto-oncogene
Molecular function	Cyclin
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G1 phase of mitotic cell cycle Traceable author statement. Source: Reactome G1/S transition of mitotic cell cycle Inferred from direct assay Ref.16. Source: UniProtKB Leydig cell differentiation Inferred from electronic annotation. Source: Compara S phase of mitotic cell cycle Traceable author statement. Source: Reactome canonical Wnt receptor signaling pathway Inferred from electronic annotation. Source: Compara cell division Inferred from electronic annotation. Source: UniProtKB-KW endoplasmic reticulum unfolded protein response Inferred from electronic annotation. Source: Compara fat cell differentiation Inferred from electronic annotation. Source: Compara lactation Inferred from electronic annotation. Source: Compara liver development Inferred from electronic annotation. Source: Compara mammary gland alveolus development Inferred from electronic annotation. Source: Compara mammary gland epithelial cell proliferation Inferred from electronic annotation. Source: Compara mitotic G1 DNA damage checkpoint Inferred from direct assay Ref.16. Source: UniProtKB negative regulation of Wnt receptor signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of epithelial cell differentiation Inferred from electronic annotation. Source: Compara organ regeneration Inferred from electronic annotation. Source: Compara positive regulation of cyclin-dependent protein kinase activity Inferred from direct assay PubMed 8114739. Source: BHF-UCL positive regulation of mammary gland epithelial cell proliferation Inferred from electronic annotation. Source: Compara re-entry into mitotic cell cycle Inferred from electronic annotation. Source: Compara regulation of G1/S transition of mitotic cell cycle Inferred from electronic annotation. Source: Compara response to UV-A Inferred from direct assay PubMed 18483258. Source: BHF-UCL 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 expression pattern PubMed 18291362. Source: UniProtKB 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 direct assay PubMed 17420273PubMed 8114739. Source: BHF-UCL cytosol Traceable author statement. Source: Reactome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Traceable author statement. Source: Reactome tight junction Inferred from electronic annotation. Source: Compara
Molecular_function	cyclin-dependent protein serine/threonine kinase regulator activity Inferred from electronic annotation. Source: Compara protein kinase activity Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BRCA1	P38398	3	EBI-375001,EBI-349905
CDK4	P11802	10	EBI-375001,EBI-295644
CDK6	Q00534	2	EBI-375001,EBI-295663
CDKN1A	P38936	5	EBI-375001,EBI-375077
CDKN1B	P46527	2	EBI-375001,EBI-519280
Ralbp1	Q62796	2	EBI-375001,EBI-3956409	From a different organism.
UHRF2	Q96PU4	4	EBI-375001,EBI-625304

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_0000080430

Regions

Domain

28 – 152

125

Cyclin N-terminal

Compositional bias

272 – 280

9

Poly-Glu

Amino acid modifications

Modified residue

286

1

Phosphothreonine Ref.16

Cross-link

269

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Mutagenesis

286

1

T → A: Reduces ubiquitination and subsequent degradation by the proteasome; when associated with A-288. Abolishes ubiquitination and subsequent degradation following DNA damage. Ref.13 Ref.16

Mutagenesis

288

1

T → A: Reduces ubiquitination and subsequent degradation by the proteasome; when associated with A-286. Ref.13

Sequence conflict

130

1

N → G in AAA52136. Ref.3

Sequence conflict

168 – 169

2

MP → IA in M74092. Ref.2

Sequence conflict

188

1

L → S in AAA52136. Ref.3

Secondary structure

1

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295

Helix Strand Turn

Details...

Beta strand

9 – 11

3

Helix

26 – 37

12

Helix

44 – 47

4

Helix

54 – 70

17

Helix

77 – 89

13

Turn

96 – 98

3

Helix

99 – 114

16

Helix

121 – 127

7

Turn

128 – 130

3

Helix

134 – 147

14

Turn

148 – 150

3

Helix

157 – 166

10

Helix

172 – 190

19

Helix

194 – 197

4

Helix

200 – 218

19

Turn

220 – 222

3

Helix

224 – 226

3

Helix

229 – 237

9

Helix

241 – 255

15

Turn

256 – 260

5

Beta strand

261 – 263

3

Sequences

	Sequence		Length	Mass (Da)
	P24385 [UniParc]. Last modified March 1, 1992. Version 1. Checksum: 3CC00C9905F58D3A	FASTA	295	33,729
	10 20 30 40 50 60 MEHQLLCCEV ETIRRAYPDA NLLNDRVLRA MLKAEETCAP SVSYFKCVQK EVLPSMRKIV 70 80 90 100 110 120 ATWMLEVCEE QKCEEEVFPL AMNYLDRFLS LEPVKKSRLQ LLGATCMFVA SKMKETIPLT 130 140 150 160 170 180 AEKLCIYTDN SIRPEELLQM ELLLVNKLKW NLAAMTPHDF IEHFLSKMPE AEENKQIIRK 190 200 210 220 230 240 HAQTFVALCA TDVKFISNPP SMVAAGSVVA AVQGLNLRSP NNFLSYYRLT RFLSRVIKCD 250 260 270 280 290 PDCLRACQEQ IEALLESSLR QAQQNMDPKA AEEEEEEEEE VDLACTPTDV RDVDI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel cyclin encoded by a bcl1-linked candidate oncogene." Motokura T., Bloom T., Kim H.G., Jueppner H., Ruderman J.V., Kronenberg H.M., Arnold A. Nature 350:512-515(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast." Lew D.J., Dulic V., Reed S.I. Cell 66:1197-1206(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Human D-type cyclin." Xiong Y., Connolly T., Futcher B., Beach D. Cell 65:691-699(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Characterization of a candidate bcl-1 gene." Withers D.A., Harvey R.C., Faust J.B., Melnyk O., Carey K., Meeker T.C. Mol. Cell. Biol. 11:4846-4853(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"Rearrangement of CCND1 (BCL1/PRAD1) 3' untranslated region in mantle-cell lymphomas and t(11q13)-associated leukemias." Rimokh R., Berger F., Bastard C., Klein B., French M., Archimbaud E., Rouault J.-P., Santa Lucia B., Duret L., Vuillaume M. Blood 83:3689-3696(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." 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. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	NIEHS SNPs program Submitted (SEP-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[8]	"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]. Tissue: Brain and Placenta.
[9]	"The PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint." Motokura T., Arnold A. Genes Chromosomes Cancer 7:89-95(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-66. Tissue: Placenta.
[10]	"CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1." Bates S., Bonetta L., McAllan D., Parry D., Holder A., Dickson C., Peters G. Oncogene 9:71-79(1994) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CDK4 AND CDK6.
[11]	"Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines." Chesi M., Bergsagel P.L., Brents L.A., Smith C.M., Gerhard D.S., Kuehl W.M. Blood 88:674-681(1996) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN MULTIPLE MYELOMA.
[12]	"New functional activities for the p21 family of CDK inhibitors." LaBaer J., Garrett M.D., Stevenson L.F., Slingerland J.M., Sandhu C., Chou H.S., Fattaey A., Harlow E. Genes Dev. 11:847-862(1997) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CDK4 IN THE CCND1-CDK4-CDKN COMPLEX, SUBCELLULAR LOCATION, FUNCTION.
[13]	"Ubiquitination of free cyclin D1 is independent of phosphorylation on threonine 286." Germain D., Russell A., Thompson A., Hendley J. J. Biol. Chem. 275:12074-12079(2000) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION, MUTAGENESIS OF THR-286 AND THR-288.
[14]	"Cyclin-dependent kinases regulate the antiproliferative function of Smads." Matsuura I., Denissova N.G., Wang G., He D., Long J., Liu F. Nature 430:226-231(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION OF CCND1-CDK4 COMPLEX IN SMAD PHOSPHORYLATION.
[15]	"Suppression of cancer cell growth by promoting cyclin D1 degradation." Shan J., Zhao W., Gu W. Mol. Cell 36:469-476(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH USP2, UBIQUITINATION, DEUBIQUITINATION BY USP2.
[16]	"F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage." Santra M.K., Wajapeyee N., Green M.R. Nature 459:722-725(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-286, UBIQUITINATION, MUTAGENESIS OF THR-286.
[17]	"NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor." Mori T., Ikeda D.D., Fukushima T., Takenoshita S., Kochi H. Cell Cycle 10:3284-3299(2011) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION, INTERACTION WITH UHRF2.
[18]	"Crystal structure of human CDK4 in complex with a D-type cyclin." Day P.J., Cleasby A., Tickle I.J., O'Reilly M., Coyle J.E., Holding F.P., McMenamin R.L., Yon J., Chopra R., Lengauer C., Jhoti H. Proc. Natl. Acad. Sci. U.S.A. 106:4166-4170(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-271 IN COMPLEX WITH WILD TYPE AND MUTANTS ALA-172; PHE-172 AND ASP-172 CDK4.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

SHMPD

The Singapore human mutation and polymorphism database

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X59798 mRNA. Translation: CAA42470.1.
M74092 mRNA. No translation available.
M64349 mRNA. Translation: AAA52136.1.
M73554 mRNA. Translation: AAA58392.1.
Z23022 mRNA. Translation: CAA80558.1.
BT019845 mRNA. Translation: AAV38648.1.
AF511593 Genomic DNA. Translation: AAM34300.2.
BC000076 mRNA. Translation: AAH00076.1.
BC001501 mRNA. Translation: AAH01501.1.
BC014078 mRNA. Translation: AAH14078.1.
BC023620 mRNA. Translation: AAH23620.1.
BC025302 mRNA. Translation: AAH25302.1.
L09054 Genomic DNA. Translation: AAA36481.1.

IPI

IPI00028098.

PIR

A38977.

RefSeq

NP_444284.1. NM_053056.2.

UniGene

Hs.523852.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2W96	X-ray	2.30	A	1-271	[»]
2W99	X-ray	2.80	A	1-271	[»]
2W9F	X-ray	2.85	A	1-271	[»]
2W9Z	X-ray	2.45	A	16-271	[»]

ProteinModelPortal

P24385.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-123N.

IntAct

P24385. 23 interactions.

MINT

MINT-135422.

STRING

9606.ENSP00000227507.

PTM databases

PhosphoSite

P24385.

Polymorphism databases

DMDM

116152.

Proteomic databases

PaxDb

P24385.

PRIDE

P24385.

Protocols and materials databases

DNASU

595.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000227507; ENSP00000227507; ENSG00000110092.

GeneID

595.

KEGG

hsa:595.

UCSC

uc001opa.3. human.

Organism-specific databases

CTD

595.

GeneCards

GC11P069455.

HGNC

HGNC:1582. CCND1.

HPA

CAB000024.

MIM

168461. gene.
254500. phenotype.

neXtProt

NX_P24385.

Orphanet

67038. Chronic B-cell lymphocytic leukemia.
52416. Mantle cell lymphoma.

PharmGKB

PA75.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5024.

HOGENOM

HOG000008182.

HOVERGEN

HBG050837.

InParanoid

P24385.

KO

K04503.

OMA

MKETVPL.

OrthoDB

EOG4JWVF1.

PhylomeDB

P24385.

Enzyme and pathway databases

Pathway_Interaction_DB

wnt_canonical_pathway. Canonical Wnt signaling pathway.
ar_pathway. Coregulation of Androgen receptor activity.
foxm1pathway. FOXM1 transcription factor network.
trkrpathway. Neurotrophic factor-mediated Trk receptor signaling.
ps1pathway. Presenilin action in Notch and Wnt signaling.
telomerasepathway. Regulation of Telomerase.
p38gammadeltapathway. Signaling mediated by p38-gamma and p38-delta.
pi3kplctrkpathway. Trk receptor signaling mediated by PI3K and PLC-gamma.

Reactome

REACT_115566. Cell Cycle.

Gene expression databases

ArrayExpress

P24385.

Bgee

P24385.

CleanEx

HS_CCND1.

Genevestigator

P24385.

GermOnline

ENSG00000110092. Homo sapiens.

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. 1 hit.
[Graphical view]

SUPFAM

SSF47954. Cyclin_like. 2 hits.

PROSITE

PS00292. CYCLINS. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P24385.

ChEMBL

CHEMBL3610.

ChiTaRS

CCND1. human.

DrugBank

DB01169. Arsenic trioxide.

EvolutionaryTrace

P24385.

GenomeRNAi

595.

NextBio

2419.

SOURCE

Search...

Entry information

Entry name

CCND1_HUMAN

Accession

Primary (citable) accession number: P24385
Secondary accession number(s): Q6LEF0

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 1, 1992
Last sequence update:	March 1, 1992
Last modified:	May 1, 2013
This is version 148 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.