Contents 1 Gene expression 2 Protein structure 3 Function 3.1 Normal function 3.2 CDK dependent functions 3.3 CDK independent functions 4 Synthesis and degradation 5 Clinical significance 5.1 Deregulation in cancer 5.2 Therapeutic target in cancer 6 Interactions 7 See also 8 References 9 Further reading


Gene expression[edit] The CCND1 gene encodes the cyclin D1 protein. The human CCNDI gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 basepairs long, and translates into 295 amino acids.[7] Cyclin D1 is expressed in all adult human tissues with the exception of cells derived from bone marrow stem cell lines (both lymphoid and myeloid).[8][9]


Protein structure[edit] Cyclin D1 is composed of the following protein domains and motifs:[10][11] retinoblastoma protein (pRb) binding motif; cyclin box domain for cyclin-dependent kinase (CDK) binding and CDK inhibitor binding; LxxLL binding motif for co-activator recruitment; PEST sequence that may mark the protein for degradation; threonine residue (threonine 286) that controls nuclear export and protein stability.


Function[edit] 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 CDKs (Cyclin-dependent kinase). 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 tumors and may contribute to tumorigenesis.[12] Micrograph of cyclin D1 staining in a mantle cell lymphoma. Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma. Cyclin D1 has been found to be overexpressed in breast carcinoma. Its potential use as a biomarker was suggested.[13] Normal function[edit] Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle.[14] During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase.[14] Cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6. The protein dimerizes with CDK4/6 to regulate the G1/S phase transition and entry into the S-phase. CDK dependent functions[edit] The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb).[15] Cyclin D1-CDK4 inhibits pRb through phosphorylation, allowing E2F transcription factors to transcribe genes required for entry into the S phase. Inactive pRb allows cell cycle progression through the G1/S transition and allows for DNA synthesis. Cyclin D1-CDK4 also enables the activation of cyclin E-CDK2 complex by sequestering Cip/Kip family CDK inhibitory proteins p21 and p27, allowing entry into the S phase.[16] Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators.[10] CDK independent functions[edit] Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α, thyroid hormone receptor, PPARγ [17][18][19][20] and AR [21]) to regulate cell proliferation, growth, and differentiation. Cyclin D1 also binds to histone acetylases and histone deacetylases to regulate cell proliferation and cell differentiation genes [22][23][21][24] in the early to mid-G1 phase.


Synthesis and degradation[edit] Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors [25] primarily through Ras mediated pathways,[26][27][28] and hormones.[22] These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export from the nucleus.[29] Cyclin D1 is degraded via an ubiquitin-mediated proteolysis pathway at the end of the S-phase. Phosphorylation of cyclin D1’s threonine residue T286 marks the protein for export from the nucleus and proteolytic degradation.[30]


Clinical significance[edit] Deregulation in cancer[edit] Cyclin D1 overexpression has been shown to correlate with early cancer onset and tumor progression [16] and it can lead to oncogenesis by increasing anchorage-independent growth and angiogenesis via VEGF production.[31] Cyclin D1 overexpression can also down-regulate Fas expression, leading to increased chemotherapeutic resistance and protection from apoptosis.[31] An abundance of cyclin D1 can be caused by various types of deregulation, including: amplification of the CCND1 gene / overexpression of cyclin D1; chromosomal translocation of the CCND1 gene; disruption of nuclear export [32] and proteolysis of cyclin D1[33] induction of transcription by oncogenic Ras, Src, ErbB2 and STATs;[34][35][36][37] Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.[38][39] Amplification of the CCND1 gene is present in: non-small cell lung cancers (30-46%) [40][41] head and neck squamous cell carcinomas (30-50%) [42][43][44] pancreatic carcinomas (25%) [45] bladder cancer (15%) [46] pituitary adenomas (49-54%) [47][48] breast carcinoma (13%) [49][50][51] Cyclin D1 overexpression is strongly correlated to ER+ breast cancer[51] and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.[30][52][53] Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers.[11] Chromosomal translocation around the cyclin D1 gene locus is often seen in B mantle cell lymphoma. In mantle cell lymphoma, cyclin D1 is translocated to the IgH promoter[54] leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.[55][56] Therapeutic target in cancer[edit] Cyclin D1 and the mechanisms it regulates have the potential to be a therapeutic target for cancer drugs: Target Methods of Inhibition Inhibition of cyclin D1 Inhibiting translation of cyclin D1 mRNA via mTOR inhibitors [57] and RXR activators.[58][59] Inducing Cyclin D1 degradation [29] Retinoid mediated cyclin D1 degradation via the ubiquitin proteolytic pathway;[60] Differentiation-inducing factor-1 (DIF-1) induced ubiquitin-dependent degradation;[61] Inhibition of cyclin D1 protein synthesis [62][63] Inducing nuclear export of Cyclin D1 Histone deacetylase inhibitors (HDACIs) to induce nuclear export of Cyclin D1 [64] Inhibition of cyclin D1-CDK4/6 Small molecule CDK inhibitors [65][66]


Interactions[edit] Cyclin D1 has been shown to interact with: NR3C4,[67][68][69] BRCA1,[70][71] CCNDBP1,[72] CDK4,[73][74][75][76][77][78] CDK6,[73][75] ESR1[70][71][79][80] HDAC3,[68][81] HDACs[24] NEUROD1,[82] NCOA1,[83] NRF1,[84] p300,[85] PACSIN2,[86] PCNA,[87][88] PPARG,[89] RAD51,[90] RB1,[91][92] TAF1,[91][93] and NR1A2.[81]


See also[edit] Parathyroid adenoma Mantle Cell Lymphoma


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Natl. Acad. Sci. U.S.A. 97 (16): 9042–6. Bibcode:2000PNAS...97.9042C. doi:10.1073/pnas.160016897. PMC 16818 . PMID 10908655.  ^ Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR (July 1997). "Identification of CDK4 sequences involved in cyclin D1 and p16 binding". J. Biol. Chem. 272 (30): 18869–74. doi:10.1074/jbc.272.30.18869. PMID 9228064.  ^ Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME (Sep 1997). "Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4". Mol. Cell. Biol. 17 (9): 5338–47. PMC 232384 . PMID 9271411.  ^ Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ (February 1997). "CDK-independent activation of estrogen receptor by cyclin D1". Cell. 88 (3): 405–15. doi:10.1016/s0092-8674(00)81879-6. PMID 9039267.  ^ a b Lin HM, Zhao L, Cheng SY (August 2002). "Cyclin D1 Is a Ligand-independent Co-repressor for Thyroid Hormone Receptors". J. Biol. Chem. 277 (32): 28733–41. doi:10.1074/jbc.M203380200. PMID 12048199.  ^ Ratineau C, Petry MW, Mutoh H, Leiter AB (March 2002). "Cyclin D1 represses the basic helix-loop-helix transcription factor, BETA2/NeuroD". J. Biol. Chem. 277 (11): 8847–53. doi:10.1074/jbc.M110747200. PMID 11788592.  ^ Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ, Bernards R (November 1998). "Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1". Genes Dev. 12 (22): 3488–98. doi:10.1101/gad.12.22.3488. PMC 317237 . PMID 9832502.  ^ Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, Fu M, Leader JE, Quong A, Novikoff PM, Pestell RG (July 2006). "Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function". Proc. Natl. Acad. Sci. U.S.A. 103 (31): 11567–72. Bibcode:2006PNAS..10311567W. doi:10.1073/pnas.0603363103. PMC 1518800 . PMID 16864783.  ^ Fu M, Wang C, Rao M, Wu X, Bouras T, Zhang X, Li Z, Jiao X, Yang J, Li A, Perkins ND, Thimmapaya B, Kung AL, Munoz A, Giordano A, Lisanti MP, Pestell RG (Aug 2005). "Cyclin D1 represses p300 transactivation through a cyclin-dependent kinase-independent mechanism". J. Biol. Chem. 280 (33): 29728–42. doi:10.1074/jbc.M503188200. PMID 15951563.  ^ Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG (Jan 2011). "PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b". Cell Cycle. 10 (1): 73–81. doi:10.4161/cc.10.1.14243. PMC 3048077 . PMID 21200149.  ^ Matsuoka S, Yamaguchi M, Matsukage A (April 1994). "D-type cyclin-binding regions of proliferating cell nuclear antigen". J. Biol. Chem. 269 (15): 11030–6. PMID 7908906.  ^ Xiong Y, Zhang H, Beach D (August 1993). "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation". Genes Dev. 7 (8): 1572–83. doi:10.1101/gad.7.8.1572. PMID 8101826.  ^ Wang C, Pattabiraman N, Zhou JN, Fu M, Sakamaki T, Albanese C, Li Z, Wu K, Hulit J, Neumeister P, Novikoff PM, Brownlee M, Scherer PE, Jones JG, Whitney KD, Donehower LA, Harris EL, Rohan T, Johns DC, Pestell RG (Sep 2003). "Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation". Mol. Cell. Biol. 23 (17): 6159–73. doi:10.1128/mcb.23.17.6159-6173.2003. PMC 180960 . PMID 12917338.  ^ Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG (November 2010). "Alternative cyclin D1 splice forms differentially regulate the DNA damage response". Cancer Res. 70 (21): 8802–11. doi:10.1158/0008-5472.CAN-10-0312. PMC 2970762 . PMID 20940395.  ^ a b Siegert JL, Rushton JJ, Sellers WR, Kaelin WG, Robbins PD (November 2000). "Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAFII250 kinase activity". Oncogene. 19 (50): 5703–11. doi:10.1038/sj.onc.1203966. PMID 11126356.  ^ Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA (May 1993). "Physical interaction of the retinoblastoma protein with human D cyclins". Cell. 73 (3): 499–511. doi:10.1016/0092-8674(93)90137-f. PMID 8490963.  ^ Adnane J, Shao Z, Robbins PD (January 1999). "Cyclin D1 associates with the TBP-associated factor TAF(II)250 to regulate Sp1-mediated transcription". Oncogene. 18 (1): 239–47. doi:10.1038/sj.onc.1202297. PMID 9926939. 


Further reading[edit] Akita H (2002). "[Prognostic importance of altered expression of cell cycle regulators in lung cancer]". Nippon Rinsho. 60 Suppl 5: 267–71. PMID 12101670.  Chung DC (2004). "Cyclin D1 in human neuroendocrine: tumorigenesis". Ann. N. Y. Acad. Sci. 1014: 209–17. Bibcode:2004NYASA1014..209C. doi:10.1196/annals.1294.022. PMID 15153436.  Jain S, Khuri FR, Shin DM (2004). "Prevention of head and neck cancer: current status and future prospects". Curr Probl Cancer. 28 (5): 265–86. doi:10.1016/j.currproblcancer.2004.05.003. PMID 15375804.  Gladden AB, Diehl JA (2005). "Location, location, location: the role of cyclin D1 nuclear localization in cancer". J. Cell. Biochem. 96 (5): 906–13. doi:10.1002/jcb.20613. PMID 16163738.  Walker JL, Assoian RK (2005). "Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progression". Cancer Metastasis Rev. 24 (3): 383–93. doi:10.1007/s10555-005-5130-7. PMID 16258726.  Gautschi O, Ratschiller D, Gugger M, Betticher DC, Heighway J (2007). "Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation". Lung Cancer. 55 (1): 1–14. doi:10.1016/j.lungcan.2006.09.024. PMID 17070615.  Li Z, Wang C, Prendergast GC, Pestell RG (2006). "Cyclin D1 functions in cell migration". Cell Cycle. 5 (21): 2440–2. doi:10.4161/cc.5.21.3428. PMID 17106256.  Zhang T, Liu WD, Saunee NA, Breslin MB, Lan MS (2009). "Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest". J. Biol. Chem. 284 (9): 5574–81. doi:10.1074/jbc.M808843200. PMC 2645817 . PMID 19124461.  Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT (1992). "Genomic organization, chromosomal localization, and independent expression of human cyclin D genes". Genomics. 13 (3): 565–74. doi:10.1016/0888-7543(92)90126-D. PMID 1386335.  Schuuring E, Verhoeven E, Mooi WJ, Michalides RJ (1992). "Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas". Oncogene. 7 (2): 355–61. PMID 1532244.  Seto M, Yamamoto K, Iida S, Akao Y, Utsumi KR, Kubonishi I, Miyoshi I, Ohtsuki T, Yawata Y, Namba M (1992). "Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation". Oncogene. 7 (7): 1401–6. PMID 1535701.  Rosenberg CL, Wong E, Petty EM, Bale AE, Tsujimoto Y, Harris NL, Arnold A (1991). "PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma". Proc. Natl. Acad. Sci. U.S.A. 88 (21): 9638–42. Bibcode:1991PNAS...88.9638R. doi:10.1073/pnas.88.21.9638. PMC 52773 . PMID 1682919.  Xiong Y, Connolly T, Futcher B, Beach D (1991). "Human D-type cyclin". Cell. 65 (4): 691–9. doi:10.1016/0092-8674(91)90100-D. PMID 1827756.  Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC (1991). "Characterization of a candidate bcl-1 gene". Mol. Cell. Biol. 11 (10): 4846–53. PMC 361453 . PMID 1833629.  Tsujimoto Y, Yunis J, Onorato-Showe L, Erikson J, Nowell PC, Croce CM (1984). "Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation". Science. 224 (4656): 1403–6. Bibcode:1984Sci...224.1403T. doi:10.1126/science.6610211. PMID 6610211.  Hall M, Bates S, Peters G (1995). "Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins". Oncogene. 11 (8): 1581–8. PMID 7478582.  Tassan JP, Jaquenoud M, Léopold P, Schultz SJ, Nigg EA (1995). "Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C". Proc. Natl. Acad. Sci. U.S.A. 92 (19): 8871–5. Bibcode:1995PNAS...92.8871T. doi:10.1073/pnas.92.19.8871. PMC 41069 . PMID 7568034.  Fornaro M, Dell'Arciprete R, Stella M, Bucci C, Nutini M, Capri MG, Alberti S (1995). "Cloning of the gene encoding Trop-2, a cell-surface glycoprotein expressed by human carcinomas". Int. J. Cancer. 62 (5): 610–8. doi:10.1002/ijc.2910620520. PMID 7665234.  Motokura T, Arnold A (1993). "PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint". Genes Chromosomes Cancer. 7 (2): 89–95. doi:10.1002/gcc.2870070205. PMID 7687458.  v t e Cell cycle proteins Cyclin A (A1, A2) B (B1, B2, B3) D (D1, D2, D3) E (E1, E2) CDK 1 2 3 4 5 6 7 8 9 10 CDK-activating kinase CDK inhibitor INK4a/ARF (p14arf/p16, p15, p18, p19) cip/kip (p21, p27, p57) P53 p63 p73 family p53 p63 p73 Other Cdc2 Cdc25 Cdc42 Cellular apoptosis susceptibility protein E2F Maturation promoting factor Wee Cullin (CUL7) Phases and checkpoints Interphase G1 phase S phase G2 phase M phase Mitosis (Preprophase Prophase Prometaphase Metaphase Anaphase Telophase) Cytokinesis Cell cycle checkpoints Restriction point Spindle checkpoint Postreplication checkpoint Other cellular phases Apoptosis G0 phase Meiosis Retrieved from "https://en.wikipedia.org/w/index.php?title=Cyclin_D1&oldid=810413931" Categories: Genes on human chromosome 11Hidden categories: Pages with DOIs inactive since 2017


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Cyclin_D1 - Photos and All Basic Informations

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Cyclin DProtein Data BankGene NomenclatureMendelian Inheritance In ManMouse Genome InformaticsHomoloGeneGeneCardsChromosome 11 (human)ChromosomeChromosome 11 (human)Chromosome 11 (human)Genomic Location For CCND1Genomic Location For CCND1Locus (genetics)Base PairBase PairChromosome 7 (mouse)ChromosomeChromosome 7 (mouse)Genomic Location For CCND1Genomic Location For CCND1Locus (genetics)Base PairBase PairGene ExpressionGene OntologyEntrezEnsemblUniProtPubMedWikidataProteinGeneCyclin-dependent KinaseCyclin-dependent Kinase 4Cyclin-dependent Kinase 6Retinoblastoma ProteinRetinoblastoma ProteinEnlargeMicrographMantle Cell LymphomaMantle Cell LymphomaBreast CarcinomaProtein-protein InteractionAndrogen ReceptorBRCA1CCNDBP1Cyclin-dependent Kinase 4Cyclin-dependent Kinase 6Estrogen Receptor AlphaHDAC3NEUROD1Nuclear Receptor Coactivator 1NRF1P300-CBP Coactivator FamilyPACSIN2PCNAPPARGRAD51Retinoblastoma ProteinTAF1Thyroid Hormone Receptor BetaParathyroid AdenomaMantle Cell LymphomaEnsembl 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IdentifierBibcodeDigital Object IdentifierPubMed IdentifierBibcodeDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierInternational Standard Book NumberSpecial:BookSources/9780120066681PubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed 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KinaseCyclin-dependent Kinase Inhibitor ProteinCell CycleP14arfP16CDKN2BCDKN2CCDKN2DCell CycleP21CDKN1BCyclin-dependent Kinase Inhibitor 1CP53 P63 P73 FamilyP53TP63P73Cdk1Cdc25CDC42Cellular Apoptosis Susceptibility ProteinE2FMaturation Promoting FactorWee1CullinCUL7InterphaseG1 PhaseS PhaseG2 PhaseCell DivisionMitosisPreprophaseProphasePrometaphaseMetaphaseAnaphaseTelophaseCytokinesisCell Cycle CheckpointRestriction PointSpindle CheckpointPostreplication CheckpointApoptosisG0 PhaseMeiosisHelp:CategoryCategory:Genes On Human Chromosome 11Category:Pages With DOIs Inactive Since 2017Discussion About Edits From This IP Address [n]A List Of Edits Made From This IP Address [y]View The Content Page [c]Discussion About The Content Page [t]Edit This Page [e]Visit The Main Page [z]Guides To Browsing WikipediaFeatured Content – The Best Of WikipediaFind Background Information On Current EventsLoad A Random Article [x]Guidance On How To Use And Edit WikipediaFind Out About WikipediaAbout The 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