Biology:Cyclin D1

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Short description: Protein-coding gene in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs 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 was originally cloned as a breakpoint rearrangement in parathyroid adenoma[1] and was shown to be required for progression through the G1 phase of the cell cycle to induce cell migration,[10] angiogenesis[11] and to induce the Warburg effect.[12] Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle.[13] During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase.[13] 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).[14] 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.[15]

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,[16] thyroid hormone receptor, PPARγ[17][18] and AR[19] ) 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 [20][21][19][22] in the early to mid-G1 phase.

Synthesis and degradation

Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors [23] primarily through Ras-mediated pathways,[24][25][26] and hormones.[20] These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export from the nucleus.[27] Cyclin D1 is degraded by the proteasome upon phosphorylation of threonine 286 and subsequent ubiquitylation via the CRL4-AMBRA1 E3 ubiquitin ligase complex.[28]

Clinical significance

Deregulation in cancer

Cyclin D1 overexpression has been shown to correlate with early cancer onset and tumor progression [15] and it can lead to oncogenesis by increasing anchorage-independent growth and angiogenesis via VEGF production.[29] Cyclin D1 overexpression can also down-regulate Fas expression, leading to increased chemotherapeutic resistance and protection from apoptosis.[29]

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;
  • mutations in the degradation motif recognized by the CRL4-AMBRA1 E3 ubiquitin ligase;[28]
  • disruption of nuclear export[30] and proteolysis of cyclin D1;[31]
  • induction of transcription by oncogenic Ras, Src, ErbB2 and STATs;[32][33][34][35]

Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.[36][37] Amplification of the CCND1 gene is present in:

Cyclin D1 overexpression is strongly correlated to ER+ breast cancer[49] and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.[28][50][51] 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[52] leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.[53][54]

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 [55] and RXR activators.[56][57]
Inducing Cyclin D1 degradation [27] Retinoid mediated cyclin D1 degradation via the ubiquitin proteolytic pathway;[58] Differentiation-inducing factor-1 (DIF-1) induced ubiquitin-dependent degradation;[59] Inhibition of cyclin D1 protein synthesis [60][61]
Inducing nuclear export of Cyclin D1 Histone deacetylase inhibitors (HDACIs) to induce nuclear export of Cyclin D1 [62]
Inhibition of cyclin D1-CDK4/6 Small molecule CDK inhibitors [63][64]

Interactions

Cyclin D1 has been shown to interact with:


See also

  • Parathyroid adenoma
  • Mantle Cell Lymphoma

References

  1. ↑ 1.0 1.1 "A novel cyclin encoded by a bcl1-linked candidate oncogene". Nature 350 (6318): 512–5. April 1991. doi:10.1038/350512a0. PMID 1826542. Bibcode: 1991Natur.350..512M. 
  2. ↑ "Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast". Cell 66 (6): 1197–206. September 1991. doi:10.1016/0092-8674(91)90042-W. PMID 1833066. 
  3. ↑ ""CCND1" Gene". Weizmann Institute of Science. 2013. https://www.genecards.org/cgi-bin/carddisp.pl?gene=CCND1. 
  4. ↑ "Characterization of a candidate bcl-1 gene". Molecular and Cellular Biology 11 (10): 4846–53. October 1991. doi:10.1128/MCB.11.10.4846. PMID 1833629. 
  5. ↑ "Genomic organization, chromosomal localization, and independent expression of human cyclin D genes". Genomics 13 (3): 565–74. July 1992. doi:10.1016/0888-7543(92)90126-d. PMID 1386335. 
  6. ↑ 6.0 6.1 "Cyclin D as a therapeutic target in cancer". Nature Reviews. Cancer 11 (8): 558–72. July 2011. doi:10.1038/nrc3090. PMID 21734724. 
  7. ↑ 7.0 7.1 "Cyclin D1: polymorphism, aberrant splicing and cancer risk". Oncogene 25 (11): 1620–8. March 2006. doi:10.1038/sj.onc.1209371. PMID 16550162. 
  8. ↑ "Entrez Gene: CCND1 cyclin D1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=595. 
  9. ↑ "Expression and significance of Wnt signaling components and their target genes in breast carcinoma". Molecular Medicine Reports 9 (1): 137–43. January 2014. doi:10.3892/mmr.2013.1774. PMID 24190141. http://www.spandidos-publications.com/mmr/9/1/137. 
  10. ↑ "Cyclin D1 governs adhesion and motility of macrophages". Molecular Biology of the Cell 14 (5): 2005–15. May 2003. doi:10.1091/mbc.02-07-0102. PMID 12802071. 
  11. ↑ "Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells". The Journal of Biological Chemistry 277 (48): 45847–53. November 2002. doi:10.1074/jbc.M209354200. PMID 12235165. 
  12. ↑ "Cyclin D1 determines mitochondrial function in vivo". Molecular and Cellular Biology 26 (14): 5449–69. July 2006. doi:10.1128/MCB.02074-05. PMID 16809779. 
  13. ↑ 13.0 13.1 "Cyclin D1 is a nuclear protein required for cell cycle progression in G1". Genes & Development 7 (5): 812–21. May 1993. doi:10.1101/gad.7.5.812. PMID 8491378. 
  14. ↑ "Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins". Cell 71 (2): 323–34. October 1992. doi:10.1016/0092-8674(92)90360-o. PMID 1423597. 
  15. ↑ 15.0 15.1 "Cycling to cancer with cyclin D1". Cancer Biology & Therapy 1 (3): 226–31. 2002. doi:10.4161/cbt.72. PMID 12432268. 
  16. ↑ 16.0 16.1 "CDK-independent activation of estrogen receptor by cyclin D1". Cell 88 (3): 405–15. February 1997. doi:10.1016/S0092-8674(00)81879-6. PMID 9039267. 
  17. ↑ "Signal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential". Molecular Targeting and Signal Transduction. Cancer Treatment and Research. 119. 2004. pp. 217–37. doi:10.1007/1-4020-7847-1_11. ISBN 978-1-4020-7822-4. 
  18. ↑ "Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment". The Journal of Biological Chemistry 280 (17): 16934–41. April 2005. doi:10.1074/jbc.m500403200. PMID 15713663. 
  19. ↑ 19.0 19.1 19.2 "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. May 2001. doi:10.1210/mend.15.5.0641. PMID 11328859. 
  20. ↑ 20.0 20.1 "Minireview: Cyclin D1: normal and abnormal functions". Endocrinology 145 (12): 5439–47. December 2004. doi:10.1210/en.2004-0959. PMID 15331580. 
  21. ↑ "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. May 1999. doi:10.1073/pnas.96.10.5382. PMID 10318892. Bibcode: 1999PNAS...96.5382M. 
  22. ↑ 22.0 22.1 "Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment". The Journal of Biological Chemistry 280 (17): 16934–41. April 2005. doi:10.1074/jbc.M500403200. PMID 15713663. 
  23. ↑ "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. January 1996. doi:10.1091/mbc.7.1.101. PMID 8741843. 
  24. ↑ "Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein". Current Biology 7 (3): 219–21. March 1997. doi:10.1016/s0960-9822(97)70094-0. PMID 9395436. 
  25. ↑ "Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells". Nature 313 (5999): 241–3. 1985. doi:10.1038/313241a0. PMID 3918269. Bibcode: 1985Natur.313..241M. 
  26. ↑ "Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein". Nature 386 (6621): 177–81. March 1997. doi:10.1038/386177a0. PMID 9062190. Bibcode: 1997Natur.386..177P. 
  27. ↑ 27.0 27.1 "The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention". Molecular Cancer 6: 24. April 2007. doi:10.1186/1476-4598-6-24. PMID 17407548. 
  28. ↑ 28.0 28.1 28.2 Simoneschi, Daniele; Rona, Gergely; Zhou, Nan; Jeong, Yeon-Tae; Jiang, Shaowen; Milletti, Giacomo; Arbini, Arnaldo A.; O’Sullivan, Alfie et al. (2021-04-29). "CRL4AMBRA1 is a master regulator of D-type cyclins" (in en). Nature 592 (7856): 789–793. doi:10.1038/s41586-021-03445-y. ISSN 0028-0836. PMID 33854235. 
  29. ↑ 29.0 29.1 "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. 2002. PMID 12014632. 
  30. ↑ "Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation". Genes & Development 14 (24): 3102–14. December 2000. doi:10.1101/gad.854900. PMID 11124803. 
  31. ↑ "Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway". Genes & Development 11 (8): 957–72. April 1997. doi:10.1101/gad.11.8.957. PMID 9136925. 
  32. ↑ "ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo". Cancer Research 67 (9): 4364–72. May 2007. doi:10.1158/0008-5472.CAN-06-1898. PMID 17483350. 
  33. ↑ "Ras regulation of cyclin D1 promoter". Regulators and Effectors of Small GTPases, Part G. 333. 2001. 116–27. doi:10.1016/s0076-6879(01)33050-1. ISBN 9780121822347. 
  34. ↑ "Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells". The EMBO Journal 18 (5): 1367–77. March 1999. doi:10.1093/emboj/18.5.1367. PMID 10064602. 
  35. ↑ "Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions". The Journal of Biological Chemistry 270 (40): 23589–97. October 1995. doi:10.1074/jbc.270.40.23589. PMID 7559524. 
  36. ↑ "Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics". Nature Reviews. Cancer 7 (10): 750–62. October 2007. doi:10.1038/nrc2230. PMID 17891190. 
  37. ↑ "Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma". International Journal of Experimental Pathology 86 (6): 347–63. December 2005. doi:10.1111/j.0959-9673.2005.00447.x. PMID 16309541. 
  38. ↑ "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. November 2001. doi:10.1016/s0169-5002(01)00225-2. PMID 11679179. 
  39. ↑ "Expression of cyclin E and cyclin D1 in non-small cell lung cancers". Lung Cancer 31 (1): 3–8. January 2001. doi:10.1016/s0169-5002(00)00160-4. PMID 11162860. 
  40. ↑ "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. September 2001. doi:10.1007/s004320100265. PMID 11570573. 
  41. ↑ "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. November 1998. doi:10.1038/sj.onc.1202153. PMID 9811462. 
  42. ↑ "Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer". Cancer Research 55 (4): 949–56. February 1995. PMID 7850812. 
  43. ↑ "Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis". Cancer Research 57 (9): 1634–7. May 1997. PMID 9134998. 
  44. ↑ Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Advances in Cancer Research. 68. 1996. pp. 67–108. doi:10.1016/s0065-230x(08)60352-8. ISBN 9780120066681. 
  45. ↑ "Aberrant expression of G(1)/S regulators is a frequent event in sporadic pituitary adenomas". Carcinogenesis 22 (8): 1149–54. August 2001. doi:10.1093/carcin/22.8.1149. PMID 11470742. 
  46. ↑ "Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic human pituitary tumors". Clinical Cancer Research 5 (8): 2133–9. August 1999. PMID 10473097. 
  47. ↑ "Cyclin D1 in breast cancer". Breast Cancer Research and Treatment 52 (1–3): 1–15. 1998. doi:10.1023/a:1006103831990. PMID 10066068. 
  48. ↑ "Chromosome 11q13 abnormalities in human breast cancer". Cancer Surveys 18: 77–94. 1993. PMID 8013002. 
  49. ↑ 49.0 49.1 "Cyclin D1 in breast cancer pathogenesis". Journal of Clinical Oncology 23 (18): 4215–24. June 2005. doi:10.1200/JCO.2005.05.064. PMID 15961768. 
  50. ↑ "Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells". Molecular Cancer Research 1 (4): 300–11. February 2003. PMID 12612058. 
  51. ↑ "Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer". Clinical Cancer Research 5 (8): 2069–76. August 1999. PMID 10473088. 
  52. ↑ "Characterization of 4 mantle cell lymphoma cell lines". Archives of Pathology & Laboratory Medicine 127 (4): 424–31. April 2003. doi:10.5858/2003-127-0424-COMCLC. PMID 12683869. 
  53. ↑ "Chromosome translocations in multiple myeloma". Oncogene 20 (40): 5611–22. September 2001. doi:10.1038/sj.onc.1204641. PMID 11607813. 
  54. ↑ "Different mechanisms of cyclin D1 overexpression in multiple myeloma revealed by fluorescence in situ hybridization and quantitative analysis of mRNA levels". Blood 104 (4): 1120–6. August 2004. doi:10.1182/blood-2003-11-3837. PMID 15090460. 
  55. ↑ "Cyclins: roles in mitogenic signaling and oncogenic transformation". Growth Factors 24 (1): 13–9. March 2006. doi:10.1080/08977190500361812. PMID 16393691. 
  56. ↑ "Bexarotene and erlotinib for aerodigestive tract cancer". Journal of Clinical Oncology 23 (34): 8757–64. December 2005. doi:10.1200/JCO.2005.01.9521. PMID 16314636. 
  57. ↑ "Cotargeting cyclin D1 starts a new chapter in lung cancer prevention and therapy". Cancer Prevention Research 4 (6): 779–82. June 2011. doi:10.1158/1940-6207.CAPR-11-0143. PMID 21636543. 
  58. ↑ "Cyclin D1 proteolysis: a retinoid chemoprevention signal in normal, immortalized, and transformed human bronchial epithelial cells". Journal of the National Cancer Institute 91 (4): 373–9. February 1999. doi:10.1093/jnci/91.4.373. PMID 10050872. 
  59. ↑ "Differentiation-inducing factor-1 induces cyclin D1 degradation through the phosphorylation of Thr286 in squamous cell carcinoma". Experimental Cell Research 310 (2): 426–33. November 2005. doi:10.1016/j.yexcr.2005.07.024. PMID 16153639. 
  60. ↑ "Mechanism of cycloheximide inhibition of protein synthesis in a cell-free system prepared from rat liver". The Journal of Biological Chemistry 244 (16): 4480–9. August 1969. doi:10.1016/S0021-9258(18)94343-7. PMID 5806588. 
  61. ↑ "The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes". The Journal of Biological Chemistry 246 (1): 174–81. January 1971. doi:10.1016/S0021-9258(18)62546-3. PMID 5541758. 
  62. ↑ "Histone deacetylase inhibitors in cancer treatment". Anti-Cancer Drugs 13 (1): 1–13. January 2002. doi:10.1097/00001813-200201000-00001. PMID 11914636. 
  63. ↑ "Cell cycle kinases as therapeutic targets for cancer". Nature Reviews. Drug Discovery 8 (7): 547–66. July 2009. doi:10.1038/nrd2907. PMID 19568282. 
  64. ↑ "Cyclin-dependent kinase pathways as targets for cancer treatment". Journal of Clinical Oncology 24 (11): 1770–83. April 2006. doi:10.1200/JCO.2005.03.7689. PMID 16603719. 
  65. ↑ 65.0 65.1 "A central domain of cyclin D1 mediates nuclear receptor corepressor activity". Oncogene 24 (3): 431–44. January 2005. doi:10.1038/sj.onc.1208200. PMID 15558026. 
  66. ↑ "D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability". Cancer Research 59 (10): 2297–301. May 1999. PMID 10344732. 
  67. ↑ 67.0 67.1 "Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity". Cancer Research 65 (15): 6557–67. August 2005. doi:10.1158/0008-5472.CAN-05-0486. PMID 16061635. 
  68. ↑ 68.0 68.1 "Cyclin D1 determines estrogen signaling in the mammary gland in vivo". Molecular Endocrinology 27 (9): 1415–28. September 2013. doi:10.1210/me.2013-1065. PMID 23864650. 
  69. ↑ "GCIP, a novel human grap2 and cyclin D interacting protein, regulates E2F-mediated transcriptional activity". The Journal of Biological Chemistry 275 (27): 20942–8. July 2000. doi:10.1074/jbc.M002598200. PMID 10801854. 
  70. ↑ 70.0 70.1 "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes & Development 13 (22): 3027–33. November 1999. doi:10.1101/gad.13.22.3027. PMID 10580009. 
  71. ↑ "A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4". Nature 366 (6456): 704–7. December 1993. doi:10.1038/366704a0. PMID 8259215. Bibcode: 1993Natur.366..704S. 
  72. ↑ 72.0 72.1 "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene 20 (16): 2000–9. April 2001. doi:10.1038/sj.onc.1204375. PMID 11360184. 
  73. ↑ "Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1". The Journal of Biological Chemistry 273 (50): 33279–86. December 1998. doi:10.1074/jbc.273.50.33279. PMID 9837900. 
  74. ↑ "Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells". Proceedings of the National Academy of Sciences of the United States of America 97 (16): 9042–6. August 2000. doi:10.1073/pnas.160016897. PMID 10908655. Bibcode: 2000PNAS...97.9042C. 
  75. ↑ "Identification of CDK4 sequences involved in cyclin D1 and p16 binding". The Journal of Biological Chemistry 272 (30): 18869–74. July 1997. doi:10.1074/jbc.272.30.18869. PMID 9228064. 
  76. ↑ "Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4". Molecular and Cellular Biology 17 (9): 5338–47. September 1997. doi:10.1128/MCB.17.9.5338. PMID 9271411. 
  77. ↑ 77.0 77.1 "Cyclin D1 Is a Ligand-independent Co-repressor for Thyroid Hormone Receptors". The Journal of Biological Chemistry 277 (32): 28733–41. August 2002. doi:10.1074/jbc.M203380200. PMID 12048199. 
  78. ↑ "Cyclin D1 represses the basic helix-loop-helix transcription factor, BETA2/NeuroD". The Journal of Biological Chemistry 277 (11): 8847–53. March 2002. doi:10.1074/jbc.M110747200. PMID 11788592. 
  79. ↑ "Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1". Genes & Development 12 (22): 3488–98. November 1998. doi:10.1101/gad.12.22.3488. PMID 9832502. 
  80. ↑ "Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function". Proceedings of the National Academy of Sciences of the United States of America 103 (31): 11567–72. August 2006. doi:10.1073/pnas.0603363103. PMID 16864783. Bibcode: 2006PNAS..10311567W. 
  81. ↑ "Cyclin D1 represses p300 transactivation through a cyclin-dependent kinase-independent mechanism". The Journal of Biological Chemistry 280 (33): 29728–42. August 2005. doi:10.1074/jbc.M503188200. PMID 15951563. 
  82. ↑ "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. January 2011. doi:10.4161/cc.10.1.14243. PMID 21200149. 
  83. ↑ "D-type cyclin-binding regions of proliferating cell nuclear antigen". The Journal of Biological Chemistry 269 (15): 11030–6. April 1994. doi:10.1016/S0021-9258(19)78087-9. PMID 7908906. 
  84. ↑ "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation". Genes & Development 7 (8): 1572–83. August 1993. doi:10.1101/gad.7.8.1572. PMID 8101826. 
  85. ↑ "Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation". Molecular and Cellular Biology 23 (17): 6159–73. September 2003. doi:10.1128/mcb.23.17.6159-6173.2003. PMID 12917338. 
  86. ↑ "Alternative cyclin D1 splice forms differentially regulate the DNA damage response". Cancer Research 70 (21): 8802–11. November 2010. doi:10.1158/0008-5472.CAN-10-0312. PMID 20940395. 
  87. ↑ 87.0 87.1 "Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAFII250 kinase activity". Oncogene 19 (50): 5703–11. November 2000. doi:10.1038/sj.onc.1203966. PMID 11126356. 
  88. ↑ "Physical interaction of the retinoblastoma protein with human D cyclins". Cell 73 (3): 499–511. May 1993. doi:10.1016/0092-8674(93)90137-f. PMID 8490963. 
  89. ↑ "Cyclin D1 associates with the TBP-associated factor TAF(II)250 to regulate Sp1-mediated transcription". Oncogene 18 (1): 239–47. January 1999. doi:10.1038/sj.onc.1202297. PMID 9926939. 

Further reading




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