Cyclin D1

Cyclin D1
Rendering based on PDB 2W96​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2W96​, 2W99​, 2W9F​, 2W9Z​
Identifiers
Symbols	CCND1 ; BCL1; D11S287E; PRAD1; U21B31
External IDs	OMIM: 168461 MGI: 88313 HomoloGene: 1334 ChEMBL: 3610 GeneCards: CCND1 Gene
Gene ontology Molecular function • transcription corepressor activity • protein kinase activity • protein binding • transcription factor binding • cyclin-dependent protein serine/threonine kinase regulator activity • enzyme binding • protein kinase binding • protein complex binding • histone deacetylase binding • proline-rich region binding Cellular component • cyclin-dependent protein kinase holoenzyme complex • intracellular • nucleus • nucleoplasm • cytosol • bicellular tight junction • membrane • transcriptional repressor complex Biological process • G1/S transition of mitotic cell cycle • negative regulation of transcription from RNA polymerase II promoter • mitotic cell cycle • re-entry into mitotic cell cycle • liver development • positive regulation of protein phosphorylation • chromatin organization • transcription, DNA-templated • protein phosphorylation • cellular response to DNA damage stimulus • Notch signaling pathway • lactation • response to iron ion • response to X-ray • response to organonitrogen compound • positive regulation of G2/M transition of mitotic cell cycle • negative regulation of Wnt signaling pathway • negative regulation of epithelial cell differentiation • endoplasmic reticulum unfolded protein response • organ regeneration • mitotic G1 DNA damage checkpoint • response to magnesium ion • response to estradiol • response to vitamin E • Leydig cell differentiation • mammary gland epithelial cell proliferation • positive regulation of mammary gland epithelial cell proliferation • response to drug • fat cell differentiation • response to ethanol • positive regulation of cyclin-dependent protein serine/threonine kinase activity • cell division • response to corticosterone • response to calcium ion • canonical Wnt signaling pathway • mammary gland alveolus development • response to UV-A • negative regulation of cell cycle arrest Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	595	12443
Ensembl	ENSG00000110092	ENSMUSG00000070348
UniProt	P24385	P25322
RefSeq (mRNA)	NM_053056	NM_007631
RefSeq (protein)	NP_444284	NP_031657
Location (UCSC)	Chr 11: 69.64 – 69.65 Mb	Chr 7: 144.93 – 144.94 Mb
PubMed search

Cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.^[1][2]

Gene expression

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.^[3] 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).^[4][5]

Protein structure

Cyclin D1 is composed of the following protein domains and motifs:^[6][7]

• 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

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.^[8]

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.^[9]

Normal function

Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle.^[10] During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase.^[10] 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

The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb).^[11] 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.^[12]

Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators.^[6]

CDK independent functions

Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α, thyroid hormone receptor, PPARγ ^{[13][14][15][16]} and AR ^[17]) to regular cell proliferation, growth, and differentiation. Cyclin D1 also binds to histone acetylases and histone deacetylases to regulate cell proliferation and cell differentiation genes ^{[18][19][20][21]} in the early to mid-G1 phase.

Synthesis and degradation

Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors ^[22] primarily through Ras mediated pathways,^[23][24][25] and hormones.^[18] These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export form the nucleus.^[26]

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.^[27]

Clinical significance

Deregulation in cancer

Cyclin D1 overexpression has been shown to correlate with early cancer onset and tumor progression ^[12] and it can lead to oncogenesis by increasing anchorage-independent growth and angiogenesis via VEGF production.^[28] Cyclin D1 overexpression can also down-regulate Fas expression, leading to increased chemotherapeutic resistance and protection from apoptosis.^[28]

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 ^[29] and proteolysis of cyclin D1^[30]

Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.^[31][32] Amplification of the CCND1 gene is present in:

• non-small cell lung cancers (30-46%) ^[33][34]
• head and neck squamous cell carcinomas (30-50%) ^[35][36][37]
• pancreatic carcinomas (25%) ^[38]
• bladder cancer (15%) ^[39]
• pituitary adenomas (49-54%) ^[40][41]
• breast carcinoma (13%) ^[42][43][44]

Cyclin D1 overexpression is strongly correlated to ER+ breast cancer^[44] and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.^[27][45][46] Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers.^[7]

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^[47] leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.^[48][49]

Therapeutic target in cancer

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 [50] and RXR activators.[51][52]
Inducing Cyclin D1 degradation [26]	Retinoid mediated cyclin D1 degradation via the ubiquitin proteolytic pathway;[53] Differentiation-inducing factor-1 (DIF-1) induced ubiquitin-dependent degradation;[54] Inhibition of cyclin D1 protein synthesis [55][56]
Inducing nuclear export of Cyclin D1	Histone deacetylase inhibitors (HDACIs) to induce nuclear export of Cyclin D1 [57]
Inhibition of cyclin D1-CDK4/6	Small molecule CDK inhibitors [58][59]

Interactions

Cyclin D1 has been shown to interact with:

• NR3C4,^[60][61][62]
• BRCA1,^[63][64]
• CCNDBP1,^[65]
• CDK4,^{[66][67][68][69][70][71]}
• CDK6,^[66][68]
• ESR1^{[63][64][72][73]}
• HDAC3,^[61][74]
• HDACs^[21]
• NEUROD1,^[75]
• NCOA1,^[76]
• NRF1,^[77]
• p300,^[78]
• PACSIN2,^[79]
• PCNA,^[80][81]
• PPARG,^[82]
• RAD51,^[83]
• RB1,^[84][85]
• TAF1,^[84][86] and
• NR1A2.^[74]

See also

• Parathyroid adenoma
• Mantle Cell Lymphoma

References

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Further reading

• 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. 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.
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• 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.
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• 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. 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.