Interplay Between Cyclin-Dependent Kinases and E2F-Dependent Transcription

  • Jun-Yuan Ji
  • Nicholas J. Dyson
Part of the Current Cancer Research book series (CUCR)


Precise control of cell proliferation is essential for normal development and survival of all multi-cellular organisms. The deregulation of cell proliferation is a fundamental feature of all types of cancer. One of the key regulators of cell proliferation is the E2F transcription factor. E2F controls the expression of many genes that are required for cells to divide and elevated E2F activity is found in most tumor cells. The activation and inactivation of E2F are tightly linked to the activation of cyclin-dependent kinases (CDKs). In normal cells, these connections allow the periodic oscillations in CDK cycle to be coupled with temporal programs of gene expression. Multiple CDK–cyclin complexes (including CDK1/2–CycA, CDK1/2–CycB, and CDK7–CycH) have been shown to directly phosphorylate E2F or its dimerization partner DP. However, in recent genetic studies, one of the strongest modifiers of E2F-dependent phenotypes was cdk8, a kinase that had not previously been linked to E2F. In this review, we summarize the effects of CDKs on E2F1 activity and describe a model that may explain the role of CDK8–CycC in E2F regulation. Since CDKs can both increase and decrease E2F activity, understanding the interplay between E2F and CDK–cyclin complexes may suggest therapeutic approaches to efficiently block cancer cell proliferation.


Mediator Complex CDK8 Module Cyclin Complex Drive Cell Cycle Progression Transcriptional Oscillator 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Drs. Erick Morris, Gerold Schubiger, and Fajun Yang for critical comments on this review. J.Y.J. is supported by a post-doctoral fellowship from the MGH Fund for Medical Discovery. This work was supported by a grant from the NIH (RO1 GM53203). N.J.D. is the MGH Saltonstall Foundation Scholar.


  1. Akoulitchev S, Chuikov S, Reinberg D (2000) TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407: 102–106.PubMedCrossRefGoogle Scholar
  2. Ansari AZ, Koh SS, Zaman Z, et al. (2002) Transcriptional activating regions target a cyclin-dependent kinase. Proc Natl Acad Sci U S A 99: 14706–14709.PubMedCrossRefGoogle Scholar
  3. Attwooll C, Lazzerini Denchi E, Helin K (2004) The E2F family: specific functions and overlapping interests. EMBO J 23: 4709–4716.PubMedCrossRefGoogle Scholar
  4. Barski A, Cuddapah S, Cui K, et al. (2007) High-resolution profiling of histone methylations in the human genome. Cell 129: 823–837.PubMedCrossRefGoogle Scholar
  5. Bjorklund S, Gustafsson CM (2005) The yeast Mediator complex and its regulation. Trends Biochem Sci 30: 240–244.PubMedCrossRefGoogle Scholar
  6. Botz J, Zerfass-Thome K, Spitkovsky D, et al. (1996) Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter. Mol Cell Biol 16: 3401–3409.PubMedGoogle Scholar
  7. Boube M, Joulia L, Cribbs DL, et al. (2002) Evidence for a mediator of RNA polymerase II transcriptional regulation conserved from yeast to man. Cell 110: 143–151.PubMedCrossRefGoogle Scholar
  8. Bracken AP, Ciro M, Cocito A, et al. (2004) E2F target genes: unraveling the biology. Trends Biochem Sci 29: 409–417.PubMedCrossRefGoogle Scholar
  9. Burkhart DL, Sage J (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8: 671–682.PubMedCrossRefGoogle Scholar
  10. Campanero MR, Flemington EK (1997) Regulation of E2F through ubiquitin-proteasome-dependent degradation: stabilization by the pRB tumor suppressor protein. Proc Natl Acad Sci U S A 94: 2221–2226.PubMedCrossRefGoogle Scholar
  11. Chen HH, Wang YC, Fann MJ (2006) Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Mol Cell Biol 26: 2736–2745.PubMedCrossRefGoogle Scholar
  12. Chen HH, Wong YH, Geneviere AM, et al. (2007) CDK13/CDC2L5 interacts with L-type cyclins and regulates alternative splicing. Biochem Biophys Res Commun 354: 735–740.PubMedCrossRefGoogle Scholar
  13. Chi Y, Huddleston MJ, Zhang X, et al. (2001) Negative regulation of Gcn4 and Msn2 transcription factors by Srb10 cyclin-dependent kinase. Genes Dev 15: 1078–1092.PubMedCrossRefGoogle Scholar
  14. Classon M, Dyson N (2001) p107 and p130: versatile proteins with interesting pockets. Exp Cell Res 264: 135–147.PubMedCrossRefGoogle Scholar
  15. Conaway RC, Sato S, Tomomori-Sato C, et al. (2005) The mammalian Mediator complex and its role in transcriptional regulation. Trends Biochem Sci 30: 250–255.PubMedCrossRefGoogle Scholar
  16. DeGregori J, Kowalik T, Nevins JR (1995) Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes. Mol Cell Biol 15: 4215–4224.PubMedGoogle Scholar
  17. DeGregori J, Johnson DG (2006) Distinct and Overlapping Roles for E2F Family Members in Transcription, Proliferation and Apoptosis. Curr Mol Med 6: 739–748.PubMedGoogle Scholar
  18. Dimova DK, Dyson NJ (2005) The E2F transcriptional network: old acquaintances with new faces. Oncogene 24: 2810–2826.PubMedCrossRefGoogle Scholar
  19. Donner AJ, Szostek S, Hoover JM, et al. (2007) DK8 is a stimulus-specific positive coregulator of p53 target genes. Mol Cell 27: 121–133.PubMedCrossRefGoogle Scholar
  20. Dou Y, Milne TA, Tackett AJ, et al. (2005) Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121: 873–885.PubMedCrossRefGoogle Scholar
  21. Duronio RJ, O’Farrell PH, Xie JE, et al. (1995) The transcription factor E2F is required for S phase during Drosophila embryogenesis. Genes Dev 9: 1445–1455.PubMedCrossRefGoogle Scholar
  22. Dyer MA, Bremner R (2005) The search for the retinoblastoma cell of origin. Nat Rev Cancer 5: 91–101.PubMedGoogle Scholar
  23. Dynlacht BD, Flores O, Lees JA, et al. (1994) Differential regulation of E2F transactivation by cyclin/cdk2 complexes. Genes Dev 8: 1772–1786.PubMedCrossRefGoogle Scholar
  24. Dynlacht BD, Moberg K, Lees JA, et al. (1997) Specific regulation of E2F family members by cyclin-dependent kinases. Mol Cell Biol 17: 3867–3875.PubMedGoogle Scholar
  25. Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes Dev 12: 2245–2262.PubMedCrossRefGoogle Scholar
  26. Elmlund H, Baraznenok V, Lindahl M, et al. (2006) The cyclin-dependent kinase 8 module sterically blocks Mediator interactions with RNA polymerase II. Proc Natl Acad Sci U S A 103: 15788–15793.PubMedCrossRefGoogle Scholar
  27. Emili A, Ingles CJ (1995) Promoter-dependent photocross-linking of the acidic transcriptional activator E2F-1 to the TATA-binding protein. J Biol Chem 270: 13674–13680.PubMedCrossRefGoogle Scholar
  28. Firestein R, Bass AJ, Kim SY, et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 455: 547–551.PubMedCrossRefGoogle Scholar
  29. Fisher RP (2005) Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci 118: 5171–5180.PubMedCrossRefGoogle Scholar
  30. Frolov MV, Dyson NJ (2004) Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J Cell Sci 117: 2173–2181.PubMedCrossRefGoogle Scholar
  31. Fry CJ, Pearson A, Malinowski E, et al. (1999) Activation of the murine dihydrofolate reductase promoter by E2F1. A requirement for CBP recruitment. J Biol Chem 274: 15883–15891.PubMedCrossRefGoogle Scholar
  32. Fryer CJ, White JB, Jones KA (2004) Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 16: 509–520.PubMedCrossRefGoogle Scholar
  33. Geng Y, Eaton EN, Picon M, et al. (1996) Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene 12: 1173–1180.PubMedGoogle Scholar
  34. Gope R, Christensen MA, Thorson A, et al. (1990) Increased expression of the retinoblastoma gene in human colorectal carcinomas relative to normal colonic mucosa. J Natl Cancer Inst 82: 310–314.PubMedCrossRefGoogle Scholar
  35. Greenman C, Stephens P, Smith R, et al. (2007) Patterns of somatic mutation in human cancer genomes. Nature 446: 153–158.PubMedCrossRefGoogle Scholar
  36. Haase SB, Reed SI (1999) Evidence that a free-running oscillator drives G1 events in the budding yeast cell cycle. Nature 401: 394–397.PubMedGoogle Scholar
  37. Hallberg M, Polozkov GV, Hu GZ, et al. (2004) Site-specific Srb10-dependent phosphorylation of the yeast Mediator subunit Med2 regulates gene expression from the 2-microm plasmid. Proc Natl Acad Sci USA. 101: 3370–3375.PubMedCrossRefGoogle Scholar
  38. Hagemeier C, Cook A, Kouzarides T (1993) The retinoblastoma protein binds E2F residues required for activation in vivo and TBP binding in vitro. Nucleic Acids Res 21: 4998–5004.PubMedCrossRefGoogle Scholar
  39. Hahn S (2004) Structure and mechanism of the RNA polymerase II transcription machinery. Nat Struct Mol Biol 11: 394–403.PubMedCrossRefGoogle Scholar
  40. Hateboer G, Kerkhoven RM, Shvarts A, et al. (1996) Degradation of E2F by the ubiquitin-proteasome pathway: regulation by retinoblastoma family proteins and adenovirus transforming proteins. Genes Dev 10: 2960–2970.PubMedCrossRefGoogle Scholar
  41. Hengartner CJ, Myer VE, Liao SM, et al. (1998) Temporal regulation of RNA polymerase II by Srb10 and Kin28 cyclin-dependent kinases. Mol Cell 2: 43–53.PubMedCrossRefGoogle Scholar
  42. Hériché JK, Ang D, Bier E, et al. (2003) Involvement of an SCFSlmb complex in timely elimination of E2F upon initiation of DNA replication in Drosophila. BMC Genet 4: 9.PubMedCrossRefGoogle Scholar
  43. Hirst M, Kobor MS, Kuriakose N, et al. (1999) GAL4 is regulated by the RNA polymerase II holoenzyme-associated cyclin-dependent protein kinase SRB10/CDK8. Mol Cell 3: 673–678.PubMedCrossRefGoogle Scholar
  44. Hofmann F, Martelli F, Livingston DM, et al. (1996) The retinoblastoma gene product protects E2F-1 from degradation by the ubiquitin-proteasome pathway. Genes Dev 10: 2949–2959.PubMedCrossRefGoogle Scholar
  45. Hsiao KM, McMahon SL, Farnham PJ (1994) Multiple DNA elements are required for the growth regulation of the mouse E2F1 promoter. Genes Dev 8: 1526–1537.PubMedCrossRefGoogle Scholar
  46. Ianari A, Gallo R, Palma M, et al. (2004) Specific role for p300/CREB-binding protein-associated factor activity in E2F1 stabilization in response to DNA damage. J Biol Chem 279: 30830–30835.PubMedCrossRefGoogle Scholar
  47. Johnson DG, Schwarz JK, Cress WD, et al. (1993) Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 365: 349–352.PubMedCrossRefGoogle Scholar
  48. Johnson DG, Degregori J (2006) Putting the Oncogenic and Tumor Suppressive Activities of E2F into Context. Curr Mol Med 6: 731–738.PubMedGoogle Scholar
  49. Kitagawa M, Higashi H, Suzuki-Takahashi I, et al. (1995) Phosphorylation of E2F-1 by cyclin A-cdk2. Oncogene 10: 229–236.PubMedGoogle Scholar
  50. Knez J, Piluso D, Bilan P, et al. (2006) Host cell factor-1 and E2F4 interact via multiple determinants in each protein. Mol Cell Biochem 288: 79–90.PubMedCrossRefGoogle Scholar
  51. Knuesel MT, Meyer KD, Donner AJ, et al. (2009a) The human CDK8 subcomplex is a histone kinase that requires Med12 for activity and can function independently of mediator. Mol Cell Biol 29: 650–661.PubMedCrossRefGoogle Scholar
  52. Knuesel MT, Meyer KD, Bernecky C, et al. (2009b) The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes Dev 23: 439–451.PubMedCrossRefGoogle Scholar
  53. Kornberg RD (2005) Mediator and the mechanism of transcriptional activation. Trends Biochem Sci 30: 235–239.PubMedCrossRefGoogle Scholar
  54. Krek W, Ewen ME, Shirodkar S, et al. (1994) Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 78: 161–172.PubMedCrossRefGoogle Scholar
  55. Krek W, Xu G, Livingston DM (1995) Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Cell 83: 1149–1158.PubMedCrossRefGoogle Scholar
  56. Lang SE, McMahon SB, Cole MD, et al. (2001) E2F transcriptional activation requires TRRAP and GCN5 cofactors. J Biol Chem 276: 32627–32634.PubMedCrossRefGoogle Scholar
  57. Lee MG, Nurse P (1987) Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 327: 31–35.PubMedCrossRefGoogle Scholar
  58. Lee RJ, Albanese C, Fu M, 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.PubMedCrossRefGoogle Scholar
  59. Li H, Lahti JM, Valentine M, et al. (1996) Molecular cloning and chromosomal localization of the human cyclin C (CCNC) and cyclin E (CCNE) genes: deletion of the CCNC gene in human tumors. Genomics 32: 253–259.PubMedCrossRefGoogle Scholar
  60. Lin WC, Lin FT, Nevins JR (2001) Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev 15: 1833–1844.PubMedGoogle Scholar
  61. Lindeman GJ, Gaubatz S, Livingston DM, et al. (1997) The subcellular localization of E2F-4 is cell-cycle dependent. Proc Natl Acad Sci U S A 94: 5095–5100.PubMedCrossRefGoogle Scholar
  62. Lipinski MM, Jacks T (1999) The retinoblastoma gene family in differentiation and development. Oncogene 18: 7873–7882.PubMedCrossRefGoogle Scholar
  63. Liu J, Kipreos ET (2000) Evolution of cyclin-dependent kinases (CDKs) and CDK-activating kinases (CAKs): differential conservation of CAKs in yeast and metazoa. Mol Biol Evol 17: 1061–1074.PubMedGoogle Scholar
  64. Liu Y, Kung C, Fishburn J, et al. (2004) Two cyclin-dependent kinases promote RNA polymerase II transcription and formation of the scaffold complex. Mol Cell Biol 24: 1721–1735.PubMedCrossRefGoogle Scholar
  65. Loyer P, Trembley JH, Katona R, et al. (2005) Role of CDK/cyclin complexes in transcription and RNA splicing. Cell Signal 17: 1033–1051.PubMedCrossRefGoogle Scholar
  66. Luciano RL, Wilson AC (2003) HCF-1 functions as a coactivator for the zinc finger protein Krox20. J Biol Chem 278: 51116–51124.PubMedCrossRefGoogle Scholar
  67. Maiti B, Li J, de Bruin A, et al. (2005) Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem 280: 18211–18220.PubMedCrossRefGoogle Scholar
  68. Majello B, Napolitano G, De Luca P, et al. (1998) Recruitment of human TBP selectively activates RNA polymerase II TATA-dependent promoters. J Biol Chem 273: 16509–16516.PubMedCrossRefGoogle Scholar
  69. Malik S, Guermah M, Yuan CX, et al. (2004) Structural and functional organization of TRAP220, the TRAP/mediator subunit that is targeted by nuclear receptors. Mol Cell Biol 24: 8244–8254.PubMedCrossRefGoogle Scholar
  70. Malik S, Roeder RG (2005) Dynamic regulation of pol II transcription by the mammalian Mediator complex. Trends Biochem Sci 30: 256–263.PubMedCrossRefGoogle Scholar
  71. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9: 153–166.PubMedCrossRefGoogle Scholar
  72. Marti A, Wirbelauer C, Scheffner M, et al. (1999) Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation. Nat Cell Biol 1: 14–19.PubMedCrossRefGoogle Scholar
  73. Martínez-Balbás MA, Bauer UM, Nielsen SJ, et al. (2000) Regulation of E2F1 activity by acetylation. EMBO J 19: 662–671.PubMedCrossRefGoogle Scholar
  74. Milton A, Luoto K, Ingram L, et al. (2006) A functionally distinct member of the DP family of E2F subunits. Oncogene 25: 3212–3218.PubMedCrossRefGoogle Scholar
  75. Mittler G, Kremmer E, Timmers HT, et al. (2001) Novel critical role of a human Mediator complex for basal RNA polymerase II transcription. EMBO Rep 2: 808–813.PubMedCrossRefGoogle Scholar
  76. Moroni MC, Hickman ES, Lazzerini Denchi E, et al. (2001) Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 3: 552–558.PubMedCrossRefGoogle Scholar
  77. Morris EJ, Ji JY, Yang F, et al. (2008) E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 455: 552–556.PubMedCrossRefGoogle Scholar
  78. Müller H, Helin K (2000) The E2F transcription factors: key regulators of cell proliferation. Biochim Biophys Acta 1470: M1–M12.Google Scholar
  79. Müller H, Bracken AP, Vernell R, et al. (2001) E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev 15: 267–285.PubMedCrossRefGoogle Scholar
  80. Myers LC, Kornberg RD (2000) Mediator of transcriptional regulation. Annu Rev Biochem 69: 729–749.PubMedCrossRefGoogle Scholar
  81. Näär AM, Lemon BD, Tjian R (2001) Transcriptional coactivator complexes. Annu Rev Biochem 70: 475–501.PubMedCrossRefGoogle Scholar
  82. Näär AM, Taatjes DJ, Zhai W, et al. (2002) Human CRSP interacts with RNA polymerase II CTD and adopts a specific CTD-bound conformation. Genes Dev 16: 1339–1344.PubMedCrossRefGoogle Scholar
  83. Nasmyth K (1995) Evolution of the cell cycle. Philos Trans R Soc Lond B Biol Sci 349: 271–281.PubMedCrossRefGoogle Scholar
  84. Nevins JR (1992) E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science 258: 424–429.PubMedCrossRefGoogle Scholar
  85. Nevins JR (1998) Toward an understanding of the functional complexity of the E2F and retinoblastoma families. Cell Growth Differ 9: 585–593.PubMedGoogle Scholar
  86. Nevins JR (2001) The Rb/E2F pathway and cancer. Hum Mol Genet 10: 699–703.PubMedCrossRefGoogle Scholar
  87. Nurse P (1990) Universal control mechanism regulating onset of M-phase. Nature 344: 503–508.PubMedCrossRefGoogle Scholar
  88. Nurse P (2000) A long twentieth century of the cell cycle and beyond. Cell 100: 71–78.PubMedCrossRefGoogle Scholar
  89. Ohata N, Ito S, Yoshida A, et al. (2006) Highly frequent allelic loss of chromosome 6q16-23 in osteosarcoma: involvement of cyclin C in osteosarcoma. Int J Mol Med 18: 1153–1158.PubMedGoogle Scholar
  90. Ohta T, Xiong Y (2001) Phosphorylation- and Skp1-independent in vitro ubiquitination of E2F1 by multiple ROC-cullin ligases. Cancer Res 61: 1347–1353.PubMedGoogle Scholar
  91. Ohtani K, DeGregori J, Nevins JR (1995) Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci U S A 92: 12146–12150.PubMedCrossRefGoogle Scholar
  92. Orlando DA, Lin CY, Bernard A, et al. (2008) Global control of cell-cycle transcription by coupled CDK and network oscillators. Nature 453: 944–947.PubMedCrossRefGoogle Scholar
  93. Pearson A, Greenblatt J (1997) Modular organization of the E2F1 activation domain and its interaction with general transcription factors TBP and TFIIH. Oncogene 15: 2643–2658.PubMedCrossRefGoogle Scholar
  94. Pediconi N, Ianari A, Costanzo A, et al. (2003) Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nat Cell Biol 5: 552–558.PubMedCrossRefGoogle Scholar
  95. Peeper DS, Keblusek P, Helin K, et al. (1995) Phosphorylation of a specific cdk site in E2F-1 affects its electrophoretic mobility and promotes pRB-binding in vitro. Oncogene 10: 39–48.PubMedGoogle Scholar
  96. Phatnani HP, Greenleaf AL (2006) Phosphorylation and functions of the RNA polymerase II CTD. Genes Dev 20: 2922–2936.PubMedCrossRefGoogle Scholar
  97. Ren B, Cam H, Takahashi Y, et al. (2002) E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev 16: 245–256.PubMedCrossRefGoogle Scholar
  98. Ross JF, Liu X, Dynlacht BD (1999) Mechanism of transcriptional repression of E2F by the retinoblastoma tumor suppressor protein. Mol Cell 3: 195–205.PubMedCrossRefGoogle Scholar
  99. Samuelsen CO, Baraznenok V, Khorosjutina O, et al. (2003) TRAP230/ARC240 and TRAP240/ARC250 Mediator subunits are functionally conserved through evolution. Proc Natl Acad Sci U S A 100: 6422–6427.PubMedCrossRefGoogle Scholar
  100. Schulman BA, Lindstrom DL, Harlow E (1998) Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin A. Proc Natl Acad Sci U S A 95: 10453–10458.PubMedCrossRefGoogle Scholar
  101. Schulze A, Zerfass K, Spitkovsky D, et al. (1995) Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci U S A 92: 11264–11268.PubMedCrossRefGoogle Scholar
  102. Shan B, Farmer AA, Lee WH (1996) The molecular basis of E2F-1/DP-1-induced S-phase entry and apoptosis. Cell Growth Differ 7: 689–697.PubMedGoogle Scholar
  103. Sherr CJ (1996) Cancer cell cycles. Science 274: 1672–1677.PubMedCrossRefGoogle Scholar
  104. Shibutani ST, de la Cruz AF, Tran V, et al. (2008) Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S phase. Dev Cell 15: 890–900.PubMedCrossRefGoogle Scholar
  105. Shimizu M, Ichikawa E, Inoue U, et al. (1995) The G1/S boundary-specific enhancer of the rat cdc2 promoter. Mol Cell Biol 15: 2882–2892.PubMedGoogle Scholar
  106. Smith ER, Cayrou C, Huang R, et al. (2005) A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol Cell Biol 25: 9175–9188.PubMedCrossRefGoogle Scholar
  107. Stevaux O, Dyson NJ (2002) A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 14: 684–691.PubMedCrossRefGoogle Scholar
  108. Stevens C, Smith L, La Thangue NB (2003) Chk2 activates E2F-1 in response to DNA damage. Nat Cell Biol 5: 401–409.PubMedCrossRefGoogle Scholar
  109. Su AI, Wiltshire T, Batalov S, et al. (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101: 6062–6067.PubMedCrossRefGoogle Scholar
  110. Taatjes DJ, Naar AM, Andel F, 3rd, et al. (2002) Structure, function, and activator-induced conformations of the CRSP coactivator. Science 295: 1058–1062.PubMedCrossRefGoogle Scholar
  111. Taatjes DJ, Marr MT, Tjian R (2004) Regulatory diversity among metazoan co-activator complexes. Nat Rev Mol Cell Biol 5: 403–410.PubMedCrossRefGoogle Scholar
  112. Tansey WP (2001) Transcriptional activation: risky business. Genes Dev 15: 1045–1050.PubMedCrossRefGoogle Scholar
  113. Taubert S, Gorrini C, Frank SR, et al. (2004) E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Mol Cell Biol 24: 4546–4556.PubMedCrossRefGoogle Scholar
  114. Tommasi S, Pfeifer GP (1995) In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression. Mol Cell Biol 15: 6901–6913.PubMedGoogle Scholar
  115. Trimarchi JM, Lees JA (2002) Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 3: 11–20.PubMedCrossRefGoogle Scholar
  116. Tsantoulis PK, Gorgoulis VG (2005) Involvement of E2F transcription factor family in cancer. Eur J Cancer 41: 2403–2414.PubMedCrossRefGoogle Scholar
  117. Tyagi S, Chabes AL, Wysocka J, et al. (2007) E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases. Mol Cell 27: 107–119.PubMedCrossRefGoogle Scholar
  118. Urist M, Tanaka T, Poyurovsky MV, et al. (2004) p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2. Genes Dev 18: 3041–3054.PubMedCrossRefGoogle Scholar
  119. van de Peppel J, Kettelarij N, van Bakel H, et al. (2005) Mediator expression profiling epistasis reveals a signal transduction pathway with antagonistic submodules and highly specific downstream targets. Mol Cell 19: 511–522.PubMedCrossRefGoogle Scholar
  120. van den Heuvel S, Dyson NJ (2008) Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 9: 713–724.PubMedCrossRefGoogle Scholar
  121. Vandel L, Kouzarides T (1999) Residues phosphorylated by TFIIH are required for E2F-1 degradation during S-phase. EMBO J 18: 4280–4291.PubMedCrossRefGoogle Scholar
  122. Vassilev LT (2007) MDM2 inhibitors for cancer therapy. Trends Mol Med 13: 23–31.PubMedCrossRefGoogle Scholar
  123. Verona R, Moberg K, Estes S, et al. (1997) E2F activity is regulated by cell cycle-dependent changes in subcellular localization. Mol Cell Biol 17: 7268–7282.PubMedGoogle Scholar
  124. Vigo E, Muller H, Prosperini E, et al. (1999) CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase. Mol Cell Biol 19: 6379–6395.PubMedGoogle Scholar
  125. Vincent O, Kuchin S, Hong SP, et al. (2001) Interaction of the Srb10 kinase with Sip4, a transcriptional activator of gluconeogenic genes in Saccharomyces cerevisiae. Mol Cell Biol 21: 5790–5796.PubMedCrossRefGoogle Scholar
  126. Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81: 323–330.PubMedCrossRefGoogle Scholar
  127. Wilson AC (2007) Setting the stage for S phase. Mol Cell 27: 176–177.PubMedCrossRefGoogle Scholar
  128. Woychik NA, Hampsey M (2002) The RNA polymerase II machinery: structure illuminates function. Cell 108: 453–463.PubMedCrossRefGoogle Scholar
  129. Wysocka J, Myers MP, Laherty CD, et al. (2003) Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev 17: 896–911.PubMedCrossRefGoogle Scholar
  130. Xu M, Sheppard KA, Peng CY, et al. (1994) Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation. Mol Cell Biol 14: 8420–8431.PubMedGoogle Scholar
  131. Yang S, Jeung HC, Jeong HJ, et al. (2007) Identification of genes with correlated patterns of variations in DNA copy number and gene expression level in gastric cancer. Genomics 89: 451–459.PubMedCrossRefGoogle Scholar
  132. Yudkovsky N, Ranish JA, Hahn S (2000) A transcription reinitiation intermediate that is stabilized by activator. Nature 408: 225–229.PubMedCrossRefGoogle Scholar
  133. Zheng N, Fraenkel E, Pabo CO, et al. (1999) Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. Genes Dev 13: 666–674.PubMedCrossRefGoogle Scholar
  134. Zhu L (2005) Tumour suppressor retinoblastoma protein Rb: a transcriptional regulator. Eur J Cancer 41: 2415–2427.PubMedCrossRefGoogle Scholar
  135. Zhu W, Giangrande PH, Nevins JR (2004) E2Fs link the control of G1/S and G2/M transcription. EMBO J 23: 4615–4626.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of PathologyHarvard Medical School, Massachusetts General Hospital Cancer CenterCharlestownUSA
  2. 2.Department of Molecular and Cellular MedicineTexas A&M Health Science CenterCollege StationUSA

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