Description: Homo sapiens cyclin D1 (CCND1), mRNA. RefSeq Summary (NM_053056): The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of human cancers. [provided by RefSeq, Dec 2019]. Transcript (Including UTRs) Position: hg19 chr11:69,455,873-69,469,242 Size: 13,370 Total Exon Count: 5 Strand: + Coding Region Position: hg19 chr11:69,456,082-69,466,050 Size: 9,969 Coding Exon Count: 5
ID:CCND1_HUMAN DESCRIPTION: RecName: Full=G1/S-specific cyclin-D1; AltName: Full=B-cell lymphoma 1 protein; Short=BCL-1; AltName: Full=BCL-1 oncogene; AltName: Full=PRAD1 oncogene; 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 G(1)/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 G(1) phase. Hypophosphorylates RB1 in early G(1) 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. SUBUNIT: 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. INTERACTION: P38398:BRCA1; NbExp=3; IntAct=EBI-375001, EBI-349905; P11802:CDK4; NbExp=10; IntAct=EBI-375001, EBI-295644; Q00534:CDK6; NbExp=2; IntAct=EBI-375001, EBI-295663; P38936:CDKN1A; NbExp=5; IntAct=EBI-375001, EBI-375077; P46527:CDKN1B; NbExp=2; IntAct=EBI-375001, EBI-519280; Q62796:Ralbp1 (xeno); NbExp=2; IntAct=EBI-375001, EBI-3956409; Q96PU4:UHRF2; NbExp=4; IntAct=EBI-375001, EBI-625304; 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). PTM: 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. PTM: 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. DISEASE: Note=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. DISEASE: Note=A chromosomal aberration involving CCND1 may be a cause of parathyroid adenomas. Translocation t(11;11)(q13;p15) with the parathyroid hormone (PTH) enhancer. DISEASE: Defects in CCND1 are a cause of multiple myeloma (MM) [MIM:254500]. MM is 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=A chromosomal aberration involving CCND1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus. SIMILARITY: Belongs to the cyclin family. Cyclin D subfamily. SIMILARITY: Contains 1 cyclin N-terminal domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/BCL1.html"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/ccnd1/"; WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=CCND1";
advanced colorectal cancer Le Marchand L 2003, Association of the cyclin D1 A870G polymorphism with advanced colorectal cancer., JAMA. 2003 Dec;290(21):2843-8.
[PubMed 14657069]
The CCND1 870A allele may be associated with colorectal cancer, and particularly with forms of the disease that result in severe morbidity and mortality.
benzene toxicity Xu, J. N. et al. 2007, Analysis for the association between genetic polymorphisms of XRCC1, XPD, XRCC3, CCND1 and the latency of the occupational chronic benzene poisoning, Zhonghua Yu Fang Yi Xue Za Zhi 2007 41(2) 114-7.
[PubMed 17605237]
The polymorphisms of XRCC1 and CCND1 potentially modify the latency of the chronic benzene poisoning among workers exposed to benzene.
bladder cancer Ito, M. et al. 2004, Polymorphism within the cyclin D1 gene is associated with an increased risk of carcinoma in situ in patients with superficial bladder cancer., Urology. 2004 Jul;64(1):74-8.
[PubMed 15245939]
Although CCND1 polymorphism is not able to serve as a prognostic marker for bladder cancer, the CCND1 variant A allele may recessively increase the risk of carcinoma in situ incidence in patients with superficial bladder cancer.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P24385
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
BioCarta from NCI Cancer Genome Anatomy Project h_gsk3Pathway - Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages h_cellcyclePathway - Cyclins and Cell Cycle Regulation h_g1Pathway - Cell Cycle: G1/S Check Point h_wntPathway - WNT Signaling Pathway h_p53Pathway - p53 Signaling Pathway h_btg2Pathway - BTG family proteins and cell cycle regulation h_carm-erPathway - CARM1 and Regulation of the Estrogen Receptor h_RacCycDPathway - Influence of Ras and Rho proteins on G1 to S Transition
Reactome (by CSHL, EBI, and GO)
Protein P24385 (Reactome details) participates in the following event(s):
R-HSA-75823 Relocalization of nuclearly localized Cyclin D1 to the cytoplasm R-HSA-75824 Ubiquitination of Cyclin D1 R-HSA-8952058 CCND1 binds RUNX3 and displaces EP300 R-HSA-8941895 Formation of CDK4/6:CCND complexes R-HSA-75822 Relocalization of nuclearly localized phospho-(T286):cyclin D1:Cdk4 to cytoplasm R-HSA-75820 Phosphorylation of Cyclin D1 at T286 by glycogen synthase kinase-3 beta R-HSA-4395227 CCND1:CREBBP binds NOTCH1 promoter R-HSA-3215426 COPRS binds CCND1:CDK4:PRMT5:pT5-WDR77 R-HSA-3215385 CDK4 in CCND1:CDK4:PRMT5:WDR77 phosphorylates WDR77 R-HSA-8952062 CCND1 recruits HDAC4 to RUNX3 R-HSA-8952069 HDAC4 deacetylates RUNX3 R-HSA-8938867 CCND3,(CCND1,CCND2) binds RUNX1 R-HSA-8941915 Cip/Kip CDK inhibitors bind CDK4/6:CCND complexes R-HSA-9008412 CDK4 phosphorylates RUNX2 R-HSA-5205799 CCND1:CDK4:PRMT5:pT5-WDR77 methylates arginine-9 of histone H3 (H3R8) R-HSA-5661117 CCND1:CDK4:PRMT5:pT5-WDR77 methylates methyl-arginine-9 of histone H3 R-HSA-8848414 Activated PTK6 binds CDKN1B R-HSA-8848436 PTK6 phosphorylates CDKN1B R-HSA-8942607 Tyrosine kinases phosphorylate Cip/Kip inhibitors bound to CDK4/6:CCND complexes R-HSA-5205861 COPRS:CCND1:CDK4:PRMT5:pT5-WDR77 methylates arginine-4 of histone H4 (H4R3) R-HSA-8942836 CDK4/6:CCND complexes are activated by T-loop phosphorylation of CDK4/6 R-HSA-69227 Cyclin D:CDK4/6 phosphorylates RB1 and prevents RB1 binding to E2F1/2/3:DP1/2 complexes R-HSA-1226094 Cyclin D:Cdk4/6 mediated phosphorylation of p130 (RBL2) and dissociation of phosphorylated p130 (RBL2) from DP1:E2F4/5 complex R-HSA-1226095 Cyclin D:CDK4/6 mediated phosphorylation of p107 (RBL1) and dissociation of phosphorylated p107 (p-RBL1) from DP1:E2F4 complex R-HSA-8951430 RUNX3 regulates WNT signaling R-HSA-9018519 Estrogen-dependent gene expression R-HSA-69229 Ubiquitin-dependent degradation of Cyclin D1 R-HSA-8951936 RUNX3 regulates p14-ARF R-HSA-69231 Cyclin D associated events in G1 R-HSA-8878159 Transcriptional regulation by RUNX3 R-HSA-8939211 ESR-mediated signaling R-HSA-75815 Ubiquitin-dependent degradation of Cyclin D R-HSA-1912408 Pre-NOTCH Transcription and Translation R-HSA-3214858 RMTs methylate histone arginines R-HSA-6785807 Interleukin-4 and 13 signaling R-HSA-8934593 Regulation of RUNX1 Expression and Activity R-HSA-69236 G1 Phase R-HSA-212436 Generic Transcription Pathway R-HSA-9006931 Signaling by Nuclear Receptors R-HSA-69242 S Phase R-HSA-8878166 Transcriptional regulation by RUNX2 R-HSA-1912422 Pre-NOTCH Expression and Processing R-HSA-3247509 Chromatin modifying enzymes R-HSA-449147 Signaling by Interleukins R-HSA-8878171 Transcriptional regulation by RUNX1 R-HSA-187577 SCF(Skp2)-mediated degradation of p27/p21 R-HSA-8849470 PTK6 Regulates Cell Cycle R-HSA-453279 Mitotic G1-G1/S phases R-HSA-73857 RNA Polymerase II Transcription R-HSA-162582 Signal Transduction R-HSA-69278 Cell Cycle (Mitotic) R-HSA-157118 Signaling by NOTCH R-HSA-4839726 Chromatin organization R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-69202 Cyclin E associated events during G1/S transition R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry R-HSA-8848021 Signaling by PTK6 R-HSA-74160 Gene expression (Transcription) R-HSA-1640170 Cell Cycle R-HSA-168256 Immune System R-HSA-69206 G1/S Transition R-HSA-9006927 Signaling by Non-Receptor Tyrosine Kinases