Cyclin D1

See also: Cyclin D
CCND1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases CCND1, BCL1, D11S287E, PRAD1, U21B31, cyclin D1
External IDs OMIM: 168461 MGI: 88313 HomoloGene: 1334 GeneCards: CCND1
Genetically Related Diseases
multiple myeloma[1]
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_444284.1

NP_031657.1

Location (UCSC) Chr 11: 69.64 – 69.65 Mb Chr 7: 144.93 – 144.94 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

Cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.[4][5]

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.[6] 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).[7][8]

Protein structure

Cyclin D1 is composed of the following protein domains and motifs:[9][10]

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.[11]

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.[12]

Normal function

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.[9]

CDK independent functions

Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α, thyroid hormone receptor, PPARγ [16][17][18][19] and AR [20]) 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 [21][22][23][24] in the early to mid-G1 phase.

Synthesis and degradation

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.[21] These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export form 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

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.[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:

Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.[34][35] Amplification of the CCND1 gene is present in:

Cyclin D1 overexpression is strongly correlated to ER+ breast cancer[47] and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.[30][48][49] Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers.[10]

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[50] leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.[51][52]

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 [53] and RXR activators.[54][55]
Inducing Cyclin D1 degradation [29] Retinoid mediated cyclin D1 degradation via the ubiquitin proteolytic pathway;[56] Differentiation-inducing factor-1 (DIF-1) induced ubiquitin-dependent degradation;[57] Inhibition of cyclin D1 protein synthesis [58][59]
Inducing nuclear export of Cyclin D1 Histone deacetylase inhibitors (HDACIs) to induce nuclear export of Cyclin D1 [60]
Inhibition of cyclin D1-CDK4/6 Small molecule CDK inhibitors [61][62]

Interactions

Cyclin D1 has been shown to interact with:

See also

References

  1. ↑ "Diseases that are genetically associated with CCND1 view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ ""CCND1" Gene". GeneCards. "Weizmann Institute of Science". 2013. Retrieved May 6, 2015.
  7. ↑ 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 361453Freely accessible. PMID 1833629.
  8. ↑ 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.
  9. 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.
  10. 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.
  11. ↑ "Entrez Gene: CCND1 cyclin D1".
  12. ↑ 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.
  13. 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.
  14. ↑ 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.
  15. 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.
  16. ↑ 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.
  17. ↑ 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 1171185Freely accessible. PMID 10022835.
  18. ↑ 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.
  19. ↑ 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 108874Freely accessible. PMID 9488476.
  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, 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.
  22. ↑ 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 21868Freely accessible. PMID 10318892.
  23. ↑ 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.
  24. 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.
  25. ↑ 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 278616Freely accessible. PMID 8741843.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. 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 1851974Freely accessible. PMID 17407548.
  30. 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.
  31. 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.
  32. ↑ 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 317128Freely accessible. PMID 11124803.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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 2517451Freely accessible. PMID 16309541.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HG (May 1997). "Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis". Cancer Research. 57 (9): 1634–7. PMID 9134998.
  42. ↑ 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.
  43. ↑ Simpson DJ, Frost SJ, Bicknell JE, Broome JC, McNicol AM, Clayton RN, Farrell WE (Aug 2001). "Aberrant expression of G(1)/S regulators is a frequent event in sporadic pituitary adenomas". Carcinogenesis. 22 (8): 1149–54. doi:10.1093/carcin/22.8.1149. PMID 11470742.
  44. ↑ 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.
  45. ↑ Barnes DM, Gillett CE (1998). "Cyclin D1 in breast cancer". Breast Cancer Research and Treatment. 52 (1-3): 1–15. doi:10.1023/a:1006103831990. PMID 10066068.
  46. ↑ Fantl V, Smith R, Brookes S, Dickson C, Peters G (1993). "Chromosome 11q13 abnormalities in human breast cancer". Cancer Surveys. 18: 77–94. PMID 8013002.
  47. 1 2 Arnold A, Papanikolaou A (Jun 2005). "Cyclin D1 in breast cancer pathogenesis". Journal of Clinical Oncology. 23 (18): 4215–24. doi:10.1200/JCO.2005.05.064. PMID 15961768.
  48. ↑ Hodges LC, Cook JD, Lobenhofer EK, Li L, Bennett L, Bushel PR, Aldaz CM, Afshari CA, Walker CL (Feb 2003). "Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells". Molecular Cancer Research. 1 (4): 300–11. PMID 12612058.
  49. ↑ Kenny FS, Hui R, Musgrove EA, Gee JM, Blamey RW, Nicholson RI, Sutherland RL, Robertson JF (Aug 1999). "Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer". Clinical Cancer Research. 5 (8): 2069–76. PMID 10473088.
  50. ↑ Amin HM, McDonnell TJ, Medeiros LJ, Rassidakis GZ, Leventaki V, O'Connor SL, Keating MJ, Lai R (Apr 2003). "Characterization of 4 mantle cell lymphoma cell lines". Archives of Pathology & Laboratory Medicine. 127 (4): 424–31. doi:10.1043/0003-9985(2003)127<0424:COMCLC>2.0.CO;2 (inactive 2015-05-06). PMID 12683869.
  51. ↑ Bergsagel PL, Kuehl WM (Sep 2001). "Chromosome translocations in multiple myeloma". Oncogene. 20 (40): 5611–22. doi:10.1038/sj.onc.1204641. PMID 11607813.
  52. ↑ Specht K, Haralambieva E, Bink K, Kremer M, Mandl-Weber S, Koch I, Tomer R, Hofler H, Schuuring E, Kluin PM, Fend F, Quintanilla-Martinez L (Aug 2004). "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. doi:10.1182/blood-2003-11-3837. PMID 15090460.
  53. ↑ Musgrove EA (Mar 2006). "Cyclins: roles in mitogenic signaling and oncogenic transformation". Growth Factors. 24 (1): 13–9. doi:10.1080/08977190500361812. PMID 16393691.
  54. ↑ Dragnev KH, Petty WJ, Shah S, Biddle A, Desai NB, Memoli V, Rigas JR, Dmitrovsky E (Dec 2005). "Bexarotene and erlotinib for aerodigestive tract cancer". Journal of Clinical Oncology. 23 (34): 8757–64. doi:10.1200/JCO.2005.01.9521. PMID 16314636.
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  57. ↑ Mori J, Takahashi-Yanaga F, Miwa Y, Watanabe Y, Hirata M, Morimoto S, Shirasuna K, Sasaguri T (Nov 2005). "Differentiation-inducing factor-1 induces cyclin D1 degradation through the phosphorylation of Thr286 in squamous cell carcinoma". Experimental Cell Research. 310 (2): 426–33. doi:10.1016/j.yexcr.2005.07.024. PMID 16153639.
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  63. ↑ 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". Mol. Endocrinol. 15 (5): 797–811. doi:10.1210/mend.15.5.0641. PMID 11328859.
  64. 1 2 Petre-Draviam CE, Williams EB, Burd CJ, Gladden A, Moghadam H, Meller J, Diehl JA, Knudsen KE (January 2005). "A central domain of cyclin D1 mediates nuclear receptor corepressor activity". Oncogene. 24 (3): 431–44. doi:10.1038/sj.onc.1208200. PMID 15558026.
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  66. 1 2 Wang C, Fan S, Li Z, Fu M, Rao M, Ma Y, Lisanti MP, Albanese C, Katzenellenbogen BS, Kushner PJ, Weber B, Rosen EM, Pestell RG (Aug 2005). "Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity". Cancer Res. 65 (15): 6557–67. doi:10.1158/0008-5472.CAN-05-0486. PMID 16061635.
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  69. 1 2 Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E (November 1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes Dev. 13 (22): 3027–33. doi:10.1101/gad.13.22.3027. PMC 317153Freely accessible. PMID 10580009.
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  71. 1 2 Lin J, Jinno S, Okayama H (April 2001). "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene. 20 (16): 2000–9. doi:10.1038/sj.onc.1204375. PMID 11360184.
  72. ↑ Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N (December 1998). "Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1". J. Biol. Chem. 273 (50): 33279–86. doi:10.1074/jbc.273.50.33279. PMID 9837900.
  73. ↑ Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM (August 2000). "Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells". Proc. Natl. Acad. Sci. U.S.A. 97 (16): 9042–6. doi:10.1073/pnas.160016897. PMC 16818Freely accessible. PMID 10908655.
  74. ↑ 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.
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