Cyclin D1

See also: Cyclin D
Cyclin D1

Rendering based on PDB 2W96​.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CCND1 ; BCL1; D11S287E; PRAD1; U21B31
External IDs OMIM: 168461 MGI: 88313 HomoloGene: 1334 ChEMBL: 3610 GeneCards: CCND1 Gene
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 cells derived from bone marrow stem cells lines (both lymphoid and myeloid).[4][5]

Protein structure

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

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:

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

Cyclin D1 overexpression is strongly correlated to ER+ breast cancer <ref name="a15961768[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:

See also

References

  1. ↑ Motokura T, Bloom T, Kim HG, Jüppner H, Ruderman JV, Kronenberg HM, Arnold A (May 1991). "A novel cyclin encoded by a bcl1-linked candidate oncogene". Nature 350 (6318): 512–5. doi:10.1038/350512a0. PMID 1826542.
  2. ↑ Lew DJ, Dulić V, Reed SI (October 1991). "Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast". Cell 66 (6): 1197–206. doi:10.1016/0092-8674(91)90042-W. PMID 1833066.
  3. ↑ ""CCND1" Gene". GeneCards. "Weizmann Institute of Science". 2013. Retrieved "May 6, 2015". Check date values in: |access-date= (help)
  4. ↑ Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC (Oct 1991). "Characterization of a candidate bcl-1 gene". Molecular and Cellular Biology 11 (10): 4846–53. PMC 361453. PMID 1833629.
  5. ↑ Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT (Jul 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.
  6. 1 2 Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (Aug 2011). "Cyclin D as a therapeutic target in cancer". Nature Reviews. Cancer 11 (8): 558–72. doi:10.1038/nrc3090. PMID 21734724.
  7. 1 2 Knudsen KE, Diehl JA, Haiman CA, Knudsen ES (Mar 2006). "Cyclin D1: polymorphism, aberrant splicing and cancer risk". Oncogene 25 (11): 1620–8. doi:10.1038/sj.onc.1209371. PMID 16550162.
  8. ↑ "Entrez Gene: CCND1 cyclin D1".
  9. ↑ He Y, Liu Z, Qiao C, Xu M, Yu J, Li G (Jan 2014). "Expression and significance of Wnt signaling components and their target genes in breast carcinoma". Mol Med Rep 9 (1): 137–43. doi:10.3892/mmr.2013.1774. PMID 24190141.
  10. 1 2 Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (May 1993). "Cyclin D1 is a nuclear protein required for cell cycle progression in G1". Genes & Development 7 (5): 812–21. doi:10.1101/gad.7.5.812. PMID 8491378.
  11. ↑ Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ (Oct 1992). "Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins". Cell 71 (2): 323–34. doi:10.1016/0092-8674(92)90360-o. PMID 1423597.
  12. 1 2 Diehl JA (2002). "Cycling to cancer with cyclin D1". Cancer Biology & Therapy 1 (3): 226–31. doi:10.4161/cbt.72. PMID 12432268.
  13. ↑ Wang C, Li Z, Fu M, Bouras T, Pestell RG (2004). "Signal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential". Cancer Treatment and Research 119: 217–37. doi:10.1007/1-4020-7847-1_11. PMID 15164880.
  14. ↑ Zhang JM, Wei Q, Zhao X, Paterson BM (Feb 1999). "Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4". The EMBO Journal 18 (4): 926–33. doi:10.1093/emboj/18.4.926. PMC 1171185. PMID 10022835.
  15. ↑ Horstmann S, Ferrari S, Klempnauer KH (Jan 2000). "Regulation of B-Myb activity by cyclin D1". Oncogene 19 (2): 298–306. doi:10.1038/sj.onc.1203302. PMID 10645009.
  16. ↑ Inoue K, Sherr CJ (Mar 1998). "Gene expression and cell cycle arrest mediated by transcription factor DMP1 is antagonized by D-type cyclins through a cyclin-dependent-kinase-independent mechanism". Molecular and Cellular Biology 18 (3): 1590–600. PMC 108874. PMID 9488476.
  17. ↑ Petre CE, Wetherill YB, Danielsen M, Knudsen KE (Jan 2002). "Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity". The Journal of Biological Chemistry 277 (3): 2207–15. doi:10.1074/jbc.M106399200. PMID 11714699.
  18. 1 2 Fu M, Wang C, Li Z, Sakamaki T, Pestell RG (Dec 2004). "Minireview: Cyclin D1: normal and abnormal functions". Endocrinology 145 (12): 5439–47. doi:10.1210/en.2004-0959. PMID 15331580.
  19. ↑ McMahon C, Suthiphongchai T, DiRenzo J, Ewen ME (May 1999). "P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor". Proceedings of the National Academy of Sciences of the United States of America 96 (10): 5382–7. doi:10.1073/pnas.96.10.5382. PMC 21868. PMID 10318892.
  20. ↑ Reutens AT, Fu M, Wang C, Albanese C, McPhaul MJ, Sun Z, Balk SP, Jänne OA, Palvimo JJ, Pestell RG (May 2001). "Cyclin D1 binds the androgen receptor and regulates hormone-dependent signaling in a p300/CBP-associated factor (P/CAF)-dependent manner". Molecular Endocrinology 15 (5): 797–811. doi:10.1210/mend.15.5.0641. PMID 11328859.
  21. 1 2 Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, Li Z, Yao TP, Pestell RG (Apr 2005). "Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment". The Journal of Biological Chemistry 280 (17): 16934–41. doi:10.1074/jbc.M500403200. PMID 15713663.
  22. ↑ Böhmer RM, Scharf E, Assoian RK (Jan 1996). "Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1". Molecular Biology of the Cell 7 (1): 101–111. doi:10.1091/mbc.7.1.101. PMC 278616. PMID 8741843.
  23. ↑ Mittnacht S, Paterson H, Olson MF, Marshall CJ (Mar 1997). "Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein". Current Biology 7 (3): 219–21. doi:10.1016/s0960-9822(97)70094-0. PMID 9395436.
  24. ↑ Mulcahy LS, Smith MR, Stacey DW (1985). "Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells". Nature 313 (5999): 241–3. doi:10.1038/313241a0. PMID 3918269.
  25. ↑ Peeper DS, Upton TM, Ladha MH, Neuman E, Zalvide J, Bernards R, DeCaprio JA, Ewen ME (Mar 1997). "Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein". Nature 386 (6621): 177–81. doi:10.1038/386177a0. PMID 9062190.
  26. 1 2 Alao JP (2007). "The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention". Molecular Cancer 6: 24. doi:10.1186/1476-4598-6-24. PMC 1851974. PMID 17407548.
  27. 1 2 Hui R, Finney GL, Carroll JS, Lee CS, Musgrove EA, Sutherland RL (Dec 2002). "Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells". Cancer Research 62 (23): 6916–23. PMID 12460907.
  28. 1 2 Shintani M, Okazaki A, Masuda T, Kawada M, Ishizuka M, Doki Y, Weinstein IB, Imoto M (2002). "Overexpression of cyclin DI contributes to malignant properties of esophageal tumor cells by increasing VEGF production and decreasing Fas expression". Anticancer Research 22 (2A): 639–47. PMID 12014632.
  29. ↑ Alt JR, Cleveland JL, Hannink M, Diehl JA (Dec 2000). "Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation". Genes & Development 14 (24): 3102–14. doi:10.1101/gad.854900. PMC 317128. PMID 11124803.
  30. ↑ Diehl JA, Zindy F, Sherr CJ (Apr 1997). "Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway". Genes & Development 11 (8): 957–72. doi:10.1101/gad.11.8.957. PMID 9136925.
  31. ↑ Jares P, Colomer D, Campo E (Oct 2007). "Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics". Nature Reviews. Cancer 7 (10): 750–62. doi:10.1038/nrc2230. PMID 17891190.
  32. ↑ Thomas GR, Nadiminti H, Regalado J (Dec 2005). "Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma". International Journal of Experimental Pathology 86 (6): 347–63. doi:10.1111/j.0959-9673.2005.00447.x. PMC 2517451. PMID 16309541.
  33. ↑ Jin M, Inoue S, Umemura T, Moriya J, Arakawa M, Nagashima K, Kato H (Nov 2001). "Cyclin D1, p16 and retinoblastoma gene product expression as a predictor for prognosis in non-small cell lung cancer at stages I and II". Lung Cancer 34 (2): 207–18. doi:10.1016/s0169-5002(01)00225-2. PMID 11679179.
  34. ↑ Yamanouchi H, Furihata M, Fujita J, Murakami H, Yoshinouchi T, Takahara J, Ohtsuki Y (Jan 2001). "Expression of cyclin E and cyclin D1 in non-small cell lung cancers". Lung Cancer 31 (1): 3–8. doi:10.1016/s0169-5002(00)00160-4. PMID 11162860.
  35. ↑ Ikeguchi M, Sakatani T, Ueta T, Kaibara N (Sep 2001). "Cyclin D1 expression and retinoblastoma gene protein (pRB) expression in esophageal squamous cell carcinoma". Journal of Cancer Research and Clinical Oncology 127 (9): 531–6. doi:10.1007/s004320100265. PMID 11570573.
  36. ↑ Izzo JG, Papadimitrakopoulou VA, Li XQ, Ibarguen H, Lee JS, Ro JY, El-Naggar A, Hong WK, Hittelman WN (Nov 1998). "Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification". Oncogene 17 (18): 2313–22. doi:10.1038/sj.onc.1202153. PMID 9811462.
  37. ↑ Bartkova J, Lukas J, Müller H, Strauss M, Gusterson B, Bartek J (Feb 1995). "Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer". Cancer Research 55 (4): 949–56. PMID 7850812.
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  39. ↑ Hall M, Peters G (1996). "Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer". Advances in Cancer Research 68: 67–108. doi:10.1016/s0065-230x(08)60352-8. PMID 8712071.
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  41. ↑ Hibberts NA, Simpson DJ, Bicknell JE, Broome JC, Hoban PR, Clayton RN, Farrell WE (Aug 1999). "Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic human pituitary tumors". Clinical Cancer Research 5 (8): 2133–9. PMID 10473097.
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  74. 1 2 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.
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