Skip to main content

Advertisement

SpringerLink
Log in

Cyclin D1, cancer progression, and opportunities in cancer treatment

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Mammalian cells encode three D cyclins (D1, D2, and D3) that coordinately function as allosteric regulators of cyclin-dependent kinase 4 (CDK4) and CDK6 to regulate cell cycle transition from G1 to S phase. Cyclin expression, accumulation, and degradation, as well as assembly and activation of CDK4/CDK6 are governed by growth factor stimulation. Cyclin D1 is more frequently dysregulated than cyclin D2 or D3 in human cancers, and as such, it has been more extensively characterized. Overexpression of cyclin D1 results in dysregulated CDK activity, rapid cell growth under conditions of restricted mitogenic signaling, bypass of key cellular checkpoints, and ultimately, neoplastic growth. This review discusses cyclin D1 transcriptional, translational, and post-translational regulations and its biological function with a particular focus on the mechanisms that result in its dysregulation in human cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Sherr CJ, Beach D, Shapiro GI (2016) Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 6:353–367

    Article  CAS  PubMed  Google Scholar 

  2. Oki T, Nishimura K, Kitaura J, Togami K, Maehara A, Izawa K, Sakaue-Sawano A, Niida A, Miyano S, Aburatani H et al (2014) A novel cell-cycle-indicator, mVenus-p27K-, identifies quiescent cells and visualizes G0-G1 transition. Sci Rep 4:4012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Brown NR, Noble ME, Endicott JA, Garman EF, Wakatsuki S, Mitchell E, Rasmussen B, Hunt T, Johnson LN (1995) The crystal structure of cyclin A. Structure 3:1235–1247

    Article  CAS  PubMed  Google Scholar 

  4. Besson A, Dowdy SF, Roberts JM (2008) CDK inhibitors: cell cycle regulators and beyond. Dev Cell 14:159–169

    Article  CAS  PubMed  Google Scholar 

  5. Kato JY, Sherr CJ (1993) Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1. Proc Natl Acad Sci U S A 90:11513–11517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Coleman ML, Marshall CJ (2001) A family outing: small GTPases cyclin’ through G1. Nat Cell Biol 3:E250–E251

    Article  CAS  PubMed  Google Scholar 

  7. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11:558–572

    Article  CAS  PubMed  Google Scholar 

  8. Xu Y, Li H, Huang C, Zhao T, Zhang H, Zheng C, Ren H, Hao J (2015) Wnt2 protein plays a role in the progression of pancreatic cancer promoted by pancreatic stellate cells. Med Oncol 32:97

    Article  PubMed  CAS  Google Scholar 

  9. Katoh M (2005) WNT2B: comparative integromics and clinical applications (review). Int J Mol Med 16:1103–1108

    PubMed  Google Scholar 

  10. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A 96:5522–5527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426

    Article  CAS  PubMed  Google Scholar 

  12. Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998) Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12:3499–3511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rimerman RA, Gellert-Randleman A, Diehl JA (2000) Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation. J Biol Chem 275:14736–14742

    Article  CAS  PubMed  Google Scholar 

  14. Weber JD, Raben DM, Phillips PJ, Baldassare JJ (1997) Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem J 326(Pt 1):61–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Poch B, Gansauge F, Schwarz A, Seufferlein T, Schnelldorfer T, Ramadani M, Beger HG, Gansauge S (2001) Epidermal growth factor induces cyclin D1 in human pancreatic carcinoma: evidence for a cyclin D1-dependent cell cycle progression. Pancreas 23:280–287

    Article  CAS  PubMed  Google Scholar 

  16. Jura N, Zhang X, Endres NF, Seeliger MA, Schindler T, Kuriyan J (2011) Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol Cell 42:9–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Perry JE, Grossmann ME, Tindall DJ (1998) Epidermal growth factor induces cyclin D1 in a human prostate cancer cell line. Prostate 35:117–124

    Article  CAS  PubMed  Google Scholar 

  18. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354

    Article  CAS  PubMed  Google Scholar 

  19. Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK 3rd, Siegel PM, Hung MC, Yarden Y et al (2000) Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 20:672–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411:1017–1021

    Article  CAS  PubMed  Google Scholar 

  21. Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O et al (2006) Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9:23–32

    Article  CAS  PubMed  Google Scholar 

  22. Dhillon S (2015) Palbociclib: first global approval. Drugs 75:543–551

    Article  CAS  PubMed  Google Scholar 

  23. Miao B, Skidan I, Yang J, Lugovskoy A, Reibarkh M, Long K, Brazell T, Durugkar KA, Maki J, Ramana CV et al (2010) Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains. Proc Natl Acad Sci U S A 107:20126–20131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takuwa N, Fukui Y, Takuwa Y (1999) Cyclin D1 expression mediated by phosphatidylinositol 3-kinase through mTOR-p70(S6K)-independent signaling in growth factor-stimulated NIH 3T3 fibroblasts. Mol Cell Biol 19:1346–1358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Daniel P, Filiz G, Brown DV, Hollande F, Gonzales M, D'Abaco G, Papalexis N, Phillips WA, Malaterre J, Ramsay RG et al (2014) Selective CREB-dependent cyclin expression mediated by the PI3K and MAPK pathways supports glioma cell proliferation. Oncogenesis 3:e108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shih VF, Tsui R, Caldwell A, Hoffmann A (2011) A single NFkappaB system for both canonical and non-canonical signaling. Cell Res 21:86–102

    Article  CAS  PubMed  Google Scholar 

  27. Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS Jr (1999) NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 19:5785–5799

  28. Karin M, Cao Y, Greten FR, Li ZW (2002) NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2:301–310

    Article  CAS  PubMed  Google Scholar 

  29. Knudsen KE, Diehl JA, Haiman CA, Knudsen ES (2006) Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 25:1620–1628

    Article  CAS  PubMed  Google Scholar 

  30. Lu F, Gladden AB, Diehl JA (2003) An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 63:7056–7061

    CAS  PubMed  Google Scholar 

  31. Olshavsky NA, Comstock CE, Schiewer MJ, Augello MA, Hyslop T, Sette C, Zhang J, Parysek LM, Knudsen KE (2010) Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. Cancer Res 70:3975–3984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Paronetto MP, Cappellari M, Busa R, Pedrotti S, Vitali R, Comstock C, Hyslop T, Knudsen KE, Sette C (2010) Alternative splicing of the cyclin D1 proto-oncogene is regulated by the RNA-binding protein Sam68. Cancer Res 70:229–239

    Article  CAS  PubMed  Google Scholar 

  33. Solomon DA, Wang Y, Fox SR, Lambeck TC, Giesting S, Lan Z, Senderowicz AM, Knudsen ES (2003) Cyclin D1 splice variants. Differential effects on localization, RB phosphorylation, and cellular transformation. J Biol Chem 278:30339–30347

    Article  CAS  PubMed  Google Scholar 

  34. Barbash O, Zamfirova P, Lin DI, Chen X, Yang K, Nakagawa H, Lu F, Rustgi AK, Diehl JA (2008) Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer. Cancer Cell 14:68–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alt JR, Cleveland JL, Hannink M, Diehl JA (2000) Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 14:3102–3114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Diehl JA, Zindy F, Sherr CJ (1997) Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 11:957–972

    Article  CAS  PubMed  Google Scholar 

  37. Aggarwal P, Lessie MD, Lin DI, Pontano L, Gladden AB, Nuskey B, Goradia A, Wasik MA, Klein-Szanto AJ, Rustgi AK et al (2007) Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev 21:2908–2922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Aggarwal P, Vaites LP, Kim JK, Mellert H, Gurung B, Nakagawa H, Herlyn M, Hua X, Rustgi AK, McMahon SB et al (2010) Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell 18:329–340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li Y, Diehl JA (2015) PRMT5-dependent p53 escape in tumorigenesis. Oncoscience 2:700–702

    Article  PubMed  PubMed Central  Google Scholar 

  40. Li Y, Chitnis N, Nakagawa H, Kita Y, Natsugoe S, Yang Y, Li Z, Wasik M, Klein-Szanto AJ, Rustgi AK et al (2015) PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov 5:288–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hindley CJ, McDowell GS, Wise H, Philpott A (2011) Regulation of cell fate determination by Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligases. Int J Dev Biol 55:249–260

    Article  CAS  PubMed  Google Scholar 

  42. Lee EK, Diehl JA (2014) SCFs in the new millennium. Oncogene 33:2011–2018

    Article  CAS  PubMed  Google Scholar 

  43. Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, Elledge SJ (1996) SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86:263–274

    Article  CAS  PubMed  Google Scholar 

  44. Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW (2004) Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev 18:2573–2580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lin DI, Barbash O, Kumar KG, Weber JD, Harper JW, Klein-Szanto AJ, Rustgi A, Fuchs SY, Diehl JA (2006) Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex. Mol Cell 24:355–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Barbash O, Diehl JA (2008) SCF(Fbx4/alphaB-crystallin) E3 ligase: when one is not enough. Cell Cycle 7:2983–2986

    Article  CAS  PubMed  Google Scholar 

  47. Lee EK, Lian Z, D'Andrea K, Letrero R, Sheng W, Liu S, Diehl JN, Pytel D, Barbash O, Schuchter L et al (2013) The FBXO4 tumor suppressor functions as a barrier to BRAFV600E-dependent metastatic melanoma. Mol Cell Biol 33:4422–4433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Barbash O, Lee EK, Diehl JA (2011) Phosphorylation-dependent regulation of SCF(Fbx4) dimerization and activity involves a novel component, 14-3-3varepsilon. Oncogene 30:1995–2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Vaites LP, Lee EK, Lian Z, Barbash O, Roy D, Wasik M, Klein-Szanto AJ, Rustgi AK, Diehl JA (2011) The Fbx4 tumor suppressor regulates cyclin D1 accumulation and prevents neoplastic transformation. Mol Cell Biol 31:4513–4523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chu X, Zhang T, Wang J, Li M, Zhang X, Tu J, Sun S, Chen X, Lu F (2014) Alternative splicing variants of human Fbx4 disturb cyclin D1 proteolysis in human cancer. Biochem Biophys Res Commun 447:158–164

    Article  CAS  PubMed  Google Scholar 

  51. Santra MK, Wajapeyee N, Green MR (2009) F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage. Nature 459:722–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pontano LL, Aggarwal P, Barbash O, Brown EJ, Bassing CH, Diehl JA (2008) Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability. Mol Cell Biol 28:7245–7258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Alt JR, Gladden AB, Diehl JA (2002) p21(Cip1) promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export. J Biol Chem 277:8517–8523

    Article  CAS  PubMed  Google Scholar 

  54. Carrano AC, Eytan E, Hershko A, Pagano M (1999) SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1:193–199

    Article  CAS  PubMed  Google Scholar 

  55. Latres E, Chiarle R, Schulman BA, Pavletich NP, Pellicer A, Inghirami G, Pagano M (2001) Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci U S A 98:2515–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M (1997) Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3:231–234

    Article  CAS  PubMed  Google Scholar 

  57. Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A (2003) Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem 278:25752–25757

    Article  CAS  PubMed  Google Scholar 

  58. ZK Y, Gervais JL, Zhang H (1998) Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins. Proc Natl Acad Sci U S A 95:11324–11329

    Article  Google Scholar 

  59. Inuzuka H, Tseng A, Gao D, Zhai B, Zhang Q, Shaik S, Wan L, Ang XL, Mock C, Yin H et al (2010) Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. Cancer Cell 18:147–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wei S, Yang HC, Chuang HC, Yang J, Kulp SK, PJ L, Lai MD, Chen CS (2008) A novel mechanism by which thiazolidinediones facilitate the proteasomal degradation of cyclin D1 in cancer cells. J Biol Chem 283:26759–26770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wei S, Lin LF, Yang CC, Wang YC, Chang GD, Chen H, Chen CS (2007) Thiazolidinediones modulate the expression of beta-catenin and other cell-cycle regulatory proteins by targeting the F-box proteins of Skp1-Cul1-F-box protein E3 ubiquitin ligase independently of peroxisome proliferator-activated receptor gamma. Mol Pharmacol 72:725–733

    Article  CAS  PubMed  Google Scholar 

  62. Yang CC, Wang YC, Wei S, Lin LF, Chen CS, Lee CC, Lin CC, Chen CS (2007) Peroxisome proliferator-activated receptor gamma-independent suppression of androgen receptor expression by troglitazone mechanism and pharmacologic exploitation. Cancer Res 67:3229–3238

    Article  CAS  PubMed  Google Scholar 

  63. McLean JR, Chaix D, Ohi MD, Gould KL (2011) State of the APC/C: organization, function, and structure. Crit Rev Biochem Mol Biol 46:118–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Agami R, Bernards R (2000) Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell 102:55–66

    Article  CAS  PubMed  Google Scholar 

  65. Kim SY, Herbst A, Tworkowski KA, Salghetti SE, Tansey WP (2003) Skp2 regulates Myc protein stability and activity. Mol Cell 11:1177–1188

    Article  CAS  PubMed  Google Scholar 

  66. von der Lehr N, Johansson S, Wu S, Bahram F, Castell A, Cetinkaya C, Hydbring P, Weidung I, Nakayama K, Nakayama KI et al (2003) The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. Mol Cell 11:1189–1200

    Article  PubMed  Google Scholar 

  67. Hakem A, Bohgaki M, Lemmers B, Tai E, Salmena L, Matysiak-Zablocki E, Jung YS, Karaskova J, Kaustov L, Duan S et al (2011) Role of Pirh2 in mediating the regulation of p53 and c-Myc. PLoS Genet 7:e1002360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Welcker M, Orian A, Jin J, Grim JE, Harper JW, Eisenman RN, Clurman BE (2004) The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci U S A 101:9085–9090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kanie T, Onoyama I, Matsumoto A, Yamada M, Nakatsumi H, Tateishi Y, Yamamura S, Tsunematsu R, Matsumoto M, Nakayama KI (2012) Genetic reevaluation of the role of F-box proteins in cyclin D1 degradation. Mol Cell Biol 32:590–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Vaites LP, Lian Z, Lee EK, Yin B, DeMicco A, Bassing CH, Diehl JA (2014) ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene 33:129–133

    Article  CAS  PubMed  Google Scholar 

  71. Jirawatnotai S, Hu Y, Michowski W, Elias JE, Becks L, Bienvenu F, Zagozdzon A, Goswami T, Wang YE, Clark AB et al (2011) A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 474:230–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Casimiro MC, Crosariol M, Loro E, Ertel A, Yu Z, Dampier W, Saria EA, Papanikolaou A, Stanek TJ, Li Z et al (2012) ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. J Clin Invest 122:833–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pytel D, Majsterek I, Diehl JA (2015) Tumor progression and the different faces of the PERK kinase. Oncogene. doi:10.1038/onc.2015.178

    PubMed  PubMed Central  Google Scholar 

  74. Brewer JW, Hendershot LM, Sherr CJ, Diehl JA (1999) Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression. Proc Natl Acad Sci U S A 96:8505–8510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904

    Article  CAS  PubMed  Google Scholar 

  76. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  CAS  PubMed  Google Scholar 

  77. Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18:7499–7509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA (2005) PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell 16:5493–5501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci U S A 97:12625–12630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Burkhart DL, Sage J (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8:671–682

    Article  CAS  PubMed  Google Scholar 

  81. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ (1993) Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 7:331–342

    Article  CAS  PubMed  Google Scholar 

  82. Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ (1992) Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71:323–334

    Article  CAS  PubMed  Google Scholar 

  83. Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM, Zhai H, Vidal M, Gygi SP, Braun P et al (2011) A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 20:620–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sheppard KE, McArthur GA (2013) The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clinical Cancer Research 19:5320–5328

    Article  CAS  PubMed  Google Scholar 

  85. Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC et al (2016) PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 165:498

    Article  CAS  PubMed  Google Scholar 

  86. Liu F (2006) Smad3 phosphorylation by cyclin-dependent kinases. Cytokine Growth Factor Rev 17:9–17

    Article  PubMed  CAS  Google Scholar 

  87. Chen CR, Kang Y, Siegel PM, Massague J (2002) E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 110:19–32

    Article  CAS  PubMed  Google Scholar 

  88. Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F (2004) Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430:226–231

    Article  CAS  PubMed  Google Scholar 

  89. Tarasewicz E, Rivas L, Hamdan R, Dokic D, Parimi V, Bernabe BP, Thomas A, Shea LD, Jeruss JS (2014) Inhibition of CDK-mediated phosphorylation of Smad3 results in decreased oncogenesis in triple negative breast cancer cells. Cell Cycle 13:3191–3201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bella L, Zona S, Nestal de Moraes G, Lam EW (2014) FOXM1: a key oncofoetal transcription factor in health and disease. Semin Cancer Biol 29:32–39

    Article  CAS  PubMed  Google Scholar 

  91. Zona S, Bella L, Burton MJ, Nestal de Moraes G, Lam EW (2014) FOXM1: an emerging master regulator of DNA damage response and genotoxic agent resistance. Biochim Biophys Acta 1839:1316–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bugno M, Daniel M, Chepelev NL, Willmore WG (2015) Changing gears in Nrf1 research, from mechanisms of regulation to its role in disease and prevention. Biochim Biophys Acta 1849:1260–1276

    Article  CAS  PubMed  Google Scholar 

  93. Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, Fu M, Leader JE, Quong A, Novikoff PM et al (2006) Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc Natl Acad Sci U S A 103:11567–11572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Otto AM (2016) Warburg effect(s)—a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metab 4:5

    Article  PubMed  PubMed Central  Google Scholar 

  95. Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY (1994) D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 14:2066–2076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Coqueret O (2002) Linking cyclins to transcriptional control. Gene 299:35–55

    Article  CAS  PubMed  Google Scholar 

  97. Lin HM, Zhao L, Cheng SY (2002) Cyclin D1 is a ligand-independent Co-repressor for thyroid hormone receptors. J Biol Chem 277:28733–28741

    Article  CAS  PubMed  Google Scholar 

  98. Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ, Bernards R (1998) Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev 12:3488–3498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Knudsen KE, Cavenee WK, Arden KC (1999) D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability. Cancer Res 59:2297–2301

    CAS  PubMed  Google Scholar 

  100. Hirai H, Sherr CJ (1996) Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1. Mol Cell Biol 16:6457–6467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pal S, Vishwanath SN, Erdjument-Bromage H, Tempst P, Sif S (2004) Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes. Mol Cell Biol 24:9630–9645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jansson M, Durant ST, Cho EC, Sheahan S, Edelmann M, Kessler B, La Thangue NB (2008) Arginine methylation regulates the p53 response. Nat Cell Biol 10:1431–1439

    Article  CAS  PubMed  Google Scholar 

  103. Kupr B, Handschin C (2015) Complex coordination of cell plasticity by a PGC-1alpha-controlled transcriptional network in skeletal muscle. Front Physiol 6:325

    Article  PubMed  PubMed Central  Google Scholar 

  104. Lee Y, Dominy JE, Choi YJ, Jurczak M, Tolliday N, Camporez JP, Chim H, Lim JH, Ruan HB, Yang X et al (2014) Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature 510:547–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Franco J, Balaji U, Freinkman E, Witkiewicz AK, Knudsen ES (2016) Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep 14:979–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hanse EA, Mashek DG, Becker JR, Solmonson AD, Mullany LK, Mashek MT, Towle HC, Chau AT, Albrecht JH (2012) Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4alpha. Cell Cycle 11:2681–2690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Mayor R, Etienne-Manneville S (2016) The front and rear of collective cell migration. Nat Rev Mol Cell Biol 17:97–109

    Article  CAS  PubMed  Google Scholar 

  108. Li Z, Wang C, Jiao X, Lu Y, Fu M, Quong AA, Dye C, Yang J, Dai M, Ju X et al (2006) Cyclin D1 regulates cellular migration through the inhibition of thrombospondin 1 and ROCK signaling. Mol Cell Biol 26:4240–4256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Larrea MD, Hong F, Wander SA, da Silva TG, Helfman D, Lannigan D, Smith JA, Slingerland JM (2009) RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility. Proc Natl Acad Sci U S A 106:9268–9273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yu Z, Wang L, Wang C, Ju X, Wang M, Chen K, Loro E, Li Z, Zhang Y, Wu K et al (2013) Cyclin D1 induction of dicer governs microRNA processing and expression in breast cancer. Nat Commun 4:2812

    PubMed  PubMed Central  Google Scholar 

  111. Santarius T, Shipley J, Brewer D, Stratton MR, Cooper CS (2010) A census of amplified and overexpressed human cancer genes. Nat Rev Cancer 10:59–64

    Article  CAS  PubMed  Google Scholar 

  112. Garcea G, Neal CP, Pattenden CJ, Steward WP, Berry DP (2005) Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer 41:2213–2236

    Article  CAS  PubMed  Google Scholar 

  113. 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 55:1–14

    Article  PubMed  Google Scholar 

  114. Li R, An SJ, Chen ZH, Zhang GC, Zhu JQ, Nie Q, Xie Z, Guo AL, Mok TS, Wu YL (2008) Expression of cyclin D1 splice variants is differentially associated with outcome in non-small cell lung cancer patients. Hum Pathol 39:1792–1801

    Article  CAS  PubMed  Google Scholar 

  115. Arnold A, Papanikolaou A (2005) Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 23:4215–4224

    Article  CAS  PubMed  Google Scholar 

  116. Hardisson D (2003) Molecular pathogenesis of head and neck squamous cell carcinoma. European Archives of Oto-Rhino-Laryngology 260:502–508

    Article  PubMed  Google Scholar 

  117. Thomas GR, Nadiminti H, Regalado J (2005) Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int J Exp Pathol 86:347–363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Li W, Sanki A, Karim RZ, Thompson JF, Soon Lee C, Zhuang L, McCarthy SW, Scolyer RA (2006) The role of cell cycle regulatory proteins in the pathogenesis of melanoma. Pathology 38:287–301

    Article  CAS  PubMed  Google Scholar 

  119. Moreno-Bueno G, Rodriguez-Perales S, Sanchez-Estevez C, Marcos R, Hardisson D, Cigudosa JC, Palacios J (2004) Molecular alterations associated with cyclin D1 overexpression in endometrial cancer. Int J Cancer 110:194–200

    Article  CAS  PubMed  Google Scholar 

  120. Wu W, Slomovitz BM, Soliman PT, Schmeler KM, Celestino J, Milam MR, KH L (2006) Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma. Int J Gynecological Cancer 16:1668–1672

    Article  CAS  Google Scholar 

  121. Bertoni F, Rinaldi A, Zucca E, Cavalli F (2006) Update on the molecular biology of mantle cell lymphoma. Hematol Oncol 24:22–27

    Article  CAS  PubMed  Google Scholar 

  122. Wiestner A, Tehrani M, Chiorazzi M, Wright G, Gibellini F, Nakayama K, Liu H, Rosenwald A, Muller-Hermelink HK, Ott G et al (2007) Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood 109:4599–4606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Benzeno S, Lu F, Guo M, Barbash O, Zhang F, Herman JG, Klein PS, Rustgi A, Diehl JA (2006) Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1. Oncogene 25:6291–6303

    Article  CAS  PubMed  Google Scholar 

  124. cBioPortal. http://wwwcbioportalorg/indexdo

  125. Moreno-Bueno G, Rodriguez-Perales S, Sanchez-Estevez C, Hardisson D, Sarrio D, Prat J, Cigudosa JC, Matias-Guiu X, Palacios J (2003) Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 22:6115–6118

    Article  CAS  PubMed  Google Scholar 

  126. Amanatullah DF, Reutens AT, Zafonte BT, Fu M, Mani S, Pestell RG (2000) Cell-cycle dysregulation and the molecular mechanisms of prostate cancer. Front Biosci J Virtual Lib 5:D372–D390

    Article  CAS  Google Scholar 

  127. Cheng M, Sexl V, Sherr CJ, Roussel MF (1998) Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1. Proc Natl Acad Sci U S A 95:1091–1096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kerkhoff E, Rapp UR (1997) Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Mol Cell Biol 17:2576–2586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Treinies I, Paterson HF, Hooper S, Wilson R, Marshall CJ (1999) Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal to stimulate DNA synthesis. Mol Cell Biol 19:321–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Aktas H, Cai H, Cooper GM (1997) Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1. Mol Cell Biol 17:3850–3857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lavoie JN, L'Allemain G, Brunet A, Muller R, Pouyssegur J (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 271:20608–20616

    Article  CAS  PubMed  Google Scholar 

  132. Liu JJ, Chao JR, Jiang MC, Ng SY, Yen JJ, Yang-Yen HF (1995) Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol Cell Biol 15:3654–3663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bandi N, Zbinden S, Gugger M, Arnold M, Kocher V, Hasan L, Kappeler A, Brunner T, Vassella E (2009) miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res 69:5553–5559

    Article  CAS  PubMed  Google Scholar 

  134. Gladden AB, Woolery R, Aggarwal P, Wasik MA, Diehl JA (2006) Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene 25:998–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bhalla K, Liu WJ, Thompson K, Anders L, Devarakonda S, Dewi R, Buckley S, Hwang BJ, Polster B, Dorsey SG et al (2014) Cyclin D1 represses gluconeogenesis via inhibition of the transcriptional coactivator PGC1alpha. Diabetes 63:3266–3278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Casimiro MC, Velasco-Velazquez M, Aguirre-Alvarado C, Pestell RG (2014) Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present. Expert Opin Investig Drugs 23:295–304

    Article  CAS  PubMed  Google Scholar 

  137. Aleem E, Arceci RJ (2015) Targeting cell cycle regulators in hematologic malignancies. Front Cell Dev Biol 3:16

    Article  PubMed  PubMed Central  Google Scholar 

  138. Zhang YX, Sicinska E, Czaplinski JT, Remillard SP, Moss S, Wang Y, Brain C, Loo A, Snyder EL, Demetri GD et al (2014) Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo. Mol Cancer Ther 13:2184–2193

    Article  CAS  PubMed  Google Scholar 

  139. Dukelow T, Kishan D, Khasraw M, Murphy CG (2015) CDK4/6 inhibitors in breast cancer. Anti-Cancer Drugs 26:797–806

    Article  CAS  PubMed  Google Scholar 

  140. Diehl JA, Ponugoti B (2010) Ubiquitin-dependent proteolysis in G1/S phase control and its relationship with tumor susceptibility. Genes Cancer 1:717–724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This paper is supported by NIH grants (Project Nos: P01 CA098101 and R01 CA093237).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St, Charleston, SC, 29425, USA

    Shuo Qie & J. Alan Diehl

Authors
  1. Shuo Qie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Alan Diehl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Alan Diehl.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qie, S., Diehl, J.A. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med 94, 1313–1326 (2016). https://doi.org/10.1007/s00109-016-1475-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-016-1475-3

Keywords

Search

Navigation