Fuzziness pp 27-49 | Cite as

Intrinsic Protein Flexibility in Regulation of Cell Proliferation: Advantages for Signaling and Opportunities for Novel Therapeutics

  • Ariele Viacava Follis
  • Charles A. Galea
  • Richard W. KriwackiEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 725)


It is now widely recognized that intrinsically disordered (or unstructured) proteins (IDPs, or IUPs) are found in organisms from all kingdoms of life. In eukaryotes, IDPs are highly abundant and perform a wide range of biological functions, including regulation and signaling. Despite increased interest in understanding the structural biology of IDPs, questions remain regarding the mechanisms through which disordered proteins perform their biological function(s). In other words, what are the relationships between disorder and function for IDPs? Several excellent reviews have recently been published that discuss the structural properties of IDPs.1, 2, 3 Here, we discuss two IDP systems which illustrate features of dynamic complexes. In the first section, we discuss two IDPs, p21 and p27, which regulate the mammalian cell division cycle by inhibiting cyclin-dependent kinases (Cdks). In the second section, we discuss recent results from Follis, Hammoudeh, Metallo and coworkers demonstrating that the IDP Myc can be bound and inhibited by small molecules through formation of dynamic complexes. Previous studies have shown that polypeptide segments of p21 and p27 are partially folded in isolation and fold further upon binding their biological targets. Interestingly, some portions of p27 which bind to and inhibit Cdk2/cyclin A remain flexible in the bound complex. This residual flexibility allows otherwise buried tyrosine residues within p27 to be phosphorylated by nonreceptor tyrosine kinases (NRTKs). Tyrosine phosphorylation relieves kinase inhibition, triggering Cdk2-mediated phosphorylation of a threonine residue within the flexible C-terminus of p27. This, in turn, marks p27 for ubiquitination and proteasomal degradation, unleashing full Cdk2 activity which drives cell cycle progression. p27, thus, constitutes a conduit for transmission of proliferative signals via posttranslational modifications. Importantly, activation of the p27 signaling conduit by oncogenic NRTKs contributes to tumorigenesis in some human cancers, including chronic myelogenous leukemia (CML)9 and breast cancer.10 Another IDP with important roles in human cancer is the proto-oncoprotein, Myc. Myc is a DNA binding transcription factor which critically drives cell proliferation in many cell types and is often deregulated in cancer. Myc is intrinsically disordered in isolation and folds upon binding another IDP, Max and DNA. Follis, Hammoudeh, Metallo and coworkers identified small molecules which bind disordered regions of Myc and inhibit its heterodimerization with Max. Importantly, these small molecules— through formation of dynamic complexes with Myc—have been shown to inhibit Myc function in vitro and in cellular assays, opening the door to IDP-targeted therapeutics in the future. The p21/p27 and Myc systems illustrate, from different perspectives, the role of dynamics in IDP function. Dynamic fluctuations are critical for p21/p27 signaling while the dynamic free state of Myc may represent a therapeutically approachable anticancer target. Herein we review the current state of knowledge related to these two topics in IDP research.


Intrinsic Disorder Intrinsic Protein Disorder Egulate Cell Drive Cell Proliferation Drive Cell Cycle Progression 
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  1. 1.
    Receveur-Brechot V, Bourhis JM, Uversky VN et al. Assessing protein disorder and induced folding. Proteins 2006; 62:24–45.PubMedGoogle Scholar
  2. 2.
    Mittag T, Forman-Kay JD. Atomic-level characterization of disordered protein ensembles. Curr Opin Struct Biol 2007; 17:3–14.PubMedGoogle Scholar
  3. 3.
    Dyson HJ, Wright PE. Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 2005; 6:197–208.PubMedGoogle Scholar
  4. 4.
    Obradovic Z, Peng K, Vucetic S et al. Exploiting heterogeneous sequence properties improves prediction of protein disorder. Proteins 2005; 61 Suppl 7:176–182.PubMedGoogle Scholar
  5. 5.
    Nair SK, Burley SK. X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 2003; 112:193–205.PubMedGoogle Scholar
  6. 6.
    Follis AV, Hammoudeh DI, Wang H et al. Structural rationale for the coupled binding and unfolding of the c-Myc oncoprotein by small molecules. Chem Biol 2008; 15:1149–1155.PubMedGoogle Scholar
  7. 7.
    Hammoudeh DI, Follis AV, Prochownik EV et al. Multiple independent binding sites for small molecule inhibitors on the c-Myc oncoprotein. J Am Chem Soc 2009; 131:7390–7401.PubMedGoogle Scholar
  8. 8.
    Yin X, Giap C, Lazo JS et al. Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene 2003; 22:6151–6159.PubMedGoogle Scholar
  9. 9.
    Clark SS, McLaughlin J, Crist WM et al. Unique forms of the abl tyrosine kinase distinguish Ph1-positive CML from Ph1-positive ALL. Science 1987; 235:85–88.PubMedGoogle Scholar
  10. 10.
    Chu I, Sun J, Arnaout A et al. P27 Phosphorylation by src regulates inhibition of cyclin E-Cdk2. Cell 2007; 128:281–294.PubMedGoogle Scholar
  11. 11.
    Kiessling A, Sperl B, Hollis A et al. Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules. Chem Biol 2006; 13:745–751.PubMedGoogle Scholar
  12. 12.
    Dunker AK, Brown CJ, Lawson JD et al. Intrinsic disorder and protein function. Biochemistry 2002; 41:6573–6582.PubMedGoogle Scholar
  13. 13.
    Tompa P. Intrinsically unstructured proteins. Trends Biochem Sci 2002; 27:527–533.PubMedGoogle Scholar
  14. 14.
    Uversky VN. Natively unfolded proteins: a point where biology waits for physics. Protein Sci 2002; 11:739–756.PubMedGoogle Scholar
  15. 15.
    Oldfield CJ, Cheng Y, Cortese MS et al. Comparing and combining predictors of mostly disordered proteins. Biochemistry 2005; 44:1989–2000.PubMedGoogle Scholar
  16. 17.
    Dunker AK, Obradovic Z, Romero P et al. Intrinsic protein disorder in complete genomes. Genome Inform Ser Workshop Genome Inform 2000; 11:161–171.PubMedGoogle Scholar
  17. 18.
    Ward JJ, Sodhi JS, McGuffin LJ et al. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 2004; 337:635–645.PubMedGoogle Scholar
  18. 19.
    Xie H, Vucetic S, Iakoucheva LM et al. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J Proteome Res 2007; 6:1882–1898.PubMedGoogle Scholar
  19. 20.
    Vucetic S, Xie H, Iakoucheva LM et al. Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes and coding sequence diversities correlated with long disordered regions. J Proteome Res 2007; 6:1899–1916.PubMedGoogle Scholar
  20. 21.
    Liu J, Perumal NB, Oldfield CJ et al. Intrinsic disorder in transcription factors. Biochemistry 2006; 45:6873–6888.PubMedGoogle Scholar
  21. 22.
    Iakoucheva LM, Brown CJ, Lawson JD et al. Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 2002; 323:573–584.PubMedGoogle Scholar
  22. 23.
    Gsponer J, Futschik ME, Teichmann SA et al. Tight regulation of unstructured proteins: from transcript synthesis to protein degradation. Science 2008; 322:1365–1368.PubMedGoogle Scholar
  23. 24.
    Vavouri T, Semple JI, Garcia-Verdugo R et al. Intrinsic protein disorder and interaction promiscuity are widely associated with dosage sensitivity. Cell 2009; 138:198–208.PubMedGoogle Scholar
  24. 25.
    Ayed A, Mulder FA, Yi GS et al. Latent and active p53 are identical in conformation. Nat Struct Biol 2001; 8:756–760.PubMedGoogle Scholar
  25. 26.
    Hoh JH. Functional protein domains from the thermally driven motion of polypeptide chains: a proposal. Proteins 1998; 32:223–228.PubMedGoogle Scholar
  26. 27.
    Tskhovrebova L, Trinick J. Titin: properties and family relationships. Nat Rev Mol Cell Biol 2003; 4:679–689.PubMedGoogle Scholar
  27. 28.
    Alber F, Dokudovskaya S, Veenhoff LM et al. The molecular architecture of the nuclear pore complex. Nature 2007; 450:695–701.PubMedGoogle Scholar
  28. 29.
    Spolar RS, Record MTJr. Coupling of local folding to site-specific binding of proteins to DNA. Science 1994; 263:777–784.PubMedGoogle Scholar
  29. 30.
    Demarest SJ, Martinez-Yamout M, Chung J et al. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 2002; 415:549–553.PubMedGoogle Scholar
  30. 31.
    Lacy ER, Filippov I, Lewis WS et al. P27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding. Nat Struct Mol Biol 2004; 11:358–364.PubMedGoogle Scholar
  31. 32.
    Tompa P, Fuxreiter M. Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 2008; 33:2–8.PubMedGoogle Scholar
  32. 33.
    Frederick KK, Marlow MS, Valentine KG et al. Conformational entropy in molecular recognition by proteins. Nature 2007; 448:325–329.PubMedGoogle Scholar
  33. 34.
    Leung DW, Rosen MK. The nucleotide switch in Cdc42 modulates coupling between the GTPase-binding and allosteric equilibria of Wiskott-Aldrich syndrome protein. Proc Natl Acad Sci USA 2005; 102:5685–5690.PubMedGoogle Scholar
  34. 35.
    Wright PE, Dyson HJ. Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 1999; 293:321–331.PubMedGoogle Scholar
  35. 36.
    Kriwacki RW, Hengst L, Tennant L et al. Structural studies of p21(waf1/cip1/sdi1) in the free and Cdk2-bound state: Conformational disorder mediates binding diversity. Proc Natl Acad Sci USA 1996; 93:11504–11509.PubMedGoogle Scholar
  36. 37.
    Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell 2008; 14:159–169.PubMedGoogle Scholar
  37. 38.
    Joerger AC, Fersht AR. Structural Biology of the Tumor Suppressor p53. Annu Rev Biochem 2008; 77:557–582.PubMedGoogle Scholar
  38. 39.
    Dunker AK, Cortese MS, Romero P et al. Flexible nets. The roles of intrinsic disorder in protein interaction networks. Febs J 2005; 272:5129–5148.PubMedGoogle Scholar
  39. 40.
    Kim PM, Sboner A, Xia Y et al. The role of disorder in interaction networks: a structural analysis. Mol Syst Biol 2008; 4:179–185.PubMedGoogle Scholar
  40. 41.
    Schnell S, Fortunato S, Roy S. Is the intrinsic disorder of proteins the cause of the scale-free architecture of protein-protein interaction networks? Proteomics 2007; 7:961–964.PubMedGoogle Scholar
  41. 42.
    Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 2004; 4:793–805.PubMedGoogle Scholar
  42. 43.
    Grimmler M, Wang Y, Mund T et al. Cdk-inhibitory activity and stability of p27(Kip1) are directly regulated by oncogenic tyrosine kinases. Cell 2007; 128:269–280.PubMedGoogle Scholar
  43. 44.
    Tompa P, Prilusky J, Silman I et al. Structural disorder serves as a weak signal for intracellular protein degradation. Proteins 2007; 71:903–909.Google Scholar
  44. 45.
    Tsvetkov P, Asher G, Paz A et al. Operational definition of intrinsically unstructured protein sequences based on susceptibility to the 20S proteasome. Proteins 2007; 70:1357–1366.Google Scholar
  45. 46.
    Lavin MF, Gueven N. The complexity of p53 stabilization and activation. Cell Death Differ 2006; 13:941–950.PubMedGoogle Scholar
  46. 47.
    Tsvetkov P, Reuven N, Shaul Y. The nanny model for IDPs. Nat Chem Biol 2009; 5:778–781.PubMedGoogle Scholar
  47. 48.
    Shoemaker BA, Portman JJ, Wolynes PG. Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc Natl Acad Sci USA 2000; 97:8868–8873.PubMedGoogle Scholar
  48. 49.
    Sugase K, Dyson HJ, Wright PE. Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature 2007; 447:1021–1025.PubMedGoogle Scholar
  49. 50.
    Huang Y, Liu Z. Kinetic advantage of intrinsically disordered proteins in coupled folding-binding process: a critical assessment of the “fly-casting” mechanism. J Mol Biol 2009; 393:1143–1159.PubMedGoogle Scholar
  50. 51.
    Hilser VJ, Thompson EB. Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins. Proc Natl Acad Sci USA 2007; 104:8311–8315.PubMedGoogle Scholar
  51. 52.
    Morgan DO. Principles of CDK regulation. Nature 1995; 374:131–134.PubMedGoogle Scholar
  52. 53.
    Sherr CJ, Roberts JM. Cdk inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13:1501–1512.PubMedGoogle Scholar
  53. 54.
    Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. Genes Dev 2004; 18:2699–2711.PubMedGoogle Scholar
  54. 55.
    Poon RY, Hunter T. Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells. Oncogene 1998; 16:1333–1343.PubMedGoogle Scholar
  55. 56.
    Reynisdottir I, Massague J. The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev 1997; 11:492–503.PubMedGoogle Scholar
  56. 57.
    Waga S, Hannon GJ, Beach D et al. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 1994; 369:574–578.PubMedGoogle Scholar
  57. 58.
    Watanabe H, Pan ZQ, Schreiber-Agus N et al. Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen. Proc Natl Acad Sci USA 1998; 95:1392–1397.PubMedGoogle Scholar
  58. 59.
    Montagnoli A, Fiore F, Eytan E et al. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev 1999; 13:1181–1189.PubMedGoogle Scholar
  59. 60.
    Nguyen H, Gitig DM, Koff A. Cell-free degradation of p27(kip1), a G1 cyclin-dependent kinase inhibitor, is dependent on CDK2 activity and the proteasome. Mol Cell Biol 1999; 19:1190–1201.PubMedGoogle Scholar
  60. 61.
    Kamura T, Hara T, Kotoshiba S et al. Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. Proc Natl Acad Sci USA 2003; 100:10231–10236.PubMedGoogle Scholar
  61. 62.
    Matsuoka S, Edwards MC, Bai C et al. P57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev 1995; 9:650–652.PubMedGoogle Scholar
  62. 63.
    Russo AA, Jeffrey PD, Patten AK et al. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 1996; 382:325–331.PubMedGoogle Scholar
  63. 64.
    Harper JW, Adams PD. Cyclin-dependent kinases. Chem Rev 2001; 101:2511–2526.PubMedGoogle Scholar
  64. 65.
    Lacy ER, Wang Y, Post J et al. Molecular Basis for the Specificity of p27 Toward Cyclin-dependent Kinases that Regulate Cell Division. J Mol Biol 2005; 349:764–773.PubMedGoogle Scholar
  65. 66.
    Adkins JN, Lumb KJ. Intrinsic structural disorder and sequence features of the cell cycle inhibitor p57Kip2. Proteins 2002; 46:1–7.PubMedGoogle Scholar
  66. 67.
    Bienkiewicz EA, Adkins JN, Lumb KJ. Functional consequences of preorganized helical structure in the intrinsically disordered cell-cycle inhibitor p27(Kip1). Biochemistry 2002; 41:752–759.PubMedGoogle Scholar
  67. 68.
    Prilusky J, Felder CE, Zeev-Ben-Mordehai T et al. FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics 2005; 21:3435–3438.PubMedGoogle Scholar
  68. 69.
    Dosztanyi Z, Csizmok V, Tompa P et al. IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 2005; 21:3433–3434.PubMedGoogle Scholar
  69. 70.
    Romero P, Obradovic Z, Li X et al. Sequence complexity of disordered protein. Proteins 2001; 42:38–48.PubMedGoogle Scholar
  70. 71.
    Harper JW, Elledge S, Keyomarsi K et al. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 1995; 6:387–400.PubMedGoogle Scholar
  71. 72.
    Polyak K, Lee MH, Erdjument-Bromage H et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 1994; 78:59–66.PubMedGoogle Scholar
  72. 73.
    Hengst L, Dulic V, Slingerland JM et al. A cell cycle-regulated inhibitor of cyclin-dependent kinases. Proc Natl Acad Sci USA 1994; 91:5291–5295.PubMedGoogle Scholar
  73. 74.
    Sivakolundu SG, Bashford D, Kriwacki RW. Disordered p27(Kip1) Exhibits Intrinsic Structure Resembling the Cdk2/Cyclin A-bound Conformation. J Mol Biol 2005; 353:1118–1128.PubMedGoogle Scholar
  74. 75.
    Galea CA, Nourse A, Wang Y et al. Role of intrinsic flexibility in signal transduction mediated by the cell cycle regulator, p27(Kip1). J Mol Biol 2007; 376:827–838.PubMedGoogle Scholar
  75. 76.
    Blain SW, Massague J. Breast cancer banishes p27 from nucleus. Nat Med 2002; 8:1076–1078.PubMedGoogle Scholar
  76. 77.
    Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 2008; 8:253–267.PubMedGoogle Scholar
  77. 78.
    Prakash S, Tian L, Ratliff KS et al. An unstructured initiation site is required for efficient proteasome-mediated degradation. Nat Struct Mol Biol 2004; 11:830–837.PubMedGoogle Scholar
  78. 79.
    Prochownik EV. c-Myc: linking transformation and genomic instability. Curr Mol Med 2008; 8:446–458.PubMedGoogle Scholar
  79. 80.
    Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer 2008; 8:976–990.PubMedGoogle Scholar
  80. 81.
    Eilers M, Eisenman RN. Myc’s broad reach. Genes Dev 2008; 22:2755–2766.PubMedGoogle Scholar
  81. 82.
    Bahram F, von der Lehr N, Cetinakaya C et al c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. Blood 2000; 95:2104–2110.PubMedGoogle Scholar
  82. 83.
    Neel BG, Hayward WS, Robiinson HL et al. Avian leukosis virus-induced tumors have common proviral intregration sites and synthesize discrete new RNAs: oncogenesis by promoter. Cell 1981; 23:323–334.PubMedGoogle Scholar
  83. 84.
    Steffen D. Proviruses are adjacent to c-myc in some murine leukemia virus-induced lymphomas. Proc Natl Acad Sci USA 1984; 81:2097–2101.PubMedGoogle Scholar
  84. 85.
    Crews S, Barth R, Hood L et al. Mouse c-myc oncogene is located on chromosome 15 and traslocated to chromosome 12 in plasmacytomas. Science 1982; 218:1319–1321.PubMedGoogle Scholar
  85. 86.
    Boxer LM, Dang CV. Translocations involving c-myc and c-myc function. Oncogene 2001; 20:5595–5610.PubMedGoogle Scholar
  86. 87.
    Collins S, Groudine M. Amplification of endogenous myc-related DNA sequences in a human myeloid leukaemia cell line. Nature 1982; 298:679–681.PubMedGoogle Scholar
  87. 88.
    Alitalo K, Shwab M, Lin CC et al. Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci USA 1983; 80:1707–1711.PubMedGoogle Scholar
  88. 89.
    Leder A, Pattengale PK, Kuo A et al. Consequences of widespread deregulation of the c-myc gene in transgenic mice: multiple neoplasms and normal development. Cell 1986; 45:485–495.PubMedGoogle Scholar
  89. 90.
    Weng AP, Millholland JM, Yashiro-Ohtani Y et al. C-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006; 20:2096–2109.PubMedGoogle Scholar
  90. 91.
    Hann SR. Role of posttranslational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function. Sem Cancer Biol 2006; 16:288–302.Google Scholar
  91. 92.
    Vervoorts J, Luscher-Firzlaff JM, Luscher B. The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem 2006; 281:34725–34729.PubMedGoogle Scholar
  92. 93.
    Dang CV. c-Myc target genes involved in cell growth, apoptosis and metabolism. Mol Cell Biol 1999; 19:1–11.PubMedGoogle Scholar
  93. 94.
    Dang CV, O’Donnell KA, Zeller KI et al. The c-Myc target gene network. Sem Cancer Biol 2006; 16:253–264.Google Scholar
  94. 95.
    Obaya AJ, Mateyak MK, Sedivy JM. Mysterious liaisons: the relationship between c-Myc and the cell cycle. Oncogene 1999; 18:2934–2941.PubMedGoogle Scholar
  95. 96.
    Luscher B, Eisenman RN. New light on Myc and Myb. Part I. Myc. Genes Dev 1990; 4:2025–2035.Google Scholar
  96. 97.
    Marcu KB, Bossone SA, Patel AJ. Myc function and regulation. Annu Rev Biochem 1992; 61:809–860.PubMedGoogle Scholar
  97. 98.
    Grandori C, Gomez-Roman N, Felton-Edkins ZA et al c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol 2005; 7:311–318.PubMedGoogle Scholar
  98. 99.
    Stone J, de Lange T, Ramsay G et al. Definition of regions in human c-myc that are involved in transformation and nuclear localization. Mol Cell Biol 1987; 7:1697–1709.PubMedGoogle Scholar
  99. 100.
    Kato GJ, Barrett J, Villa-Garcia M et al. An amino-terminal c-myc domain required for neoplastic transformation activates transcription. Mol Cell Biol 1990; 10:5914–5920.PubMedGoogle Scholar
  100. 101.
    Blackwell TK, Kretzner L, Blackwood EM et al. Sequence-specific DNA binding by the c-Myc protein. Science 1990; 250:1149–1151.PubMedGoogle Scholar
  101. 102.
    McMahon SB, Wood MA, Cole MD. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol 2000; 20:556–562.PubMedGoogle Scholar
  102. 103.
    Grace Cheng SW, Davles KP, Yung E et al. C-MYC interacts with INI1/hSNF5 and requires the SWI/ SNF complex for transactivation function. Nat Genet 1999; 22:102–105.Google Scholar
  103. 104.
    Eberhardy SR, Farnham PJ. C-Myc mediates activation of the cad promoter via a postRNA polymerase II recruitment mechanism. J Biol Chem 2001; 276:48562–48571.PubMedGoogle Scholar
  104. 105.
    Eberhardy SR, Farnham PJ. Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter. J Biol Chem 2002; 277:40156–40162.PubMedGoogle Scholar
  105. 106.
    Blackwood EM, Eisenman RN. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 1991; 251:1211–1217.PubMedGoogle Scholar
  106. 107.
    Blackwood EM, Kretzner L, Eisenman RN. Myc and Max function as a nucleoprotein complex. Curr Opin Genet Dev 1992; 2:227–235.PubMedGoogle Scholar
  107. 108.
    Amati B, Brooks MW, Levy N et al. Oncogenic activity of the c-Myc protein requires dimerization with Max. Cell 1993; 72:233–245.PubMedGoogle Scholar
  108. 109.
    Lavigne P, Crump MP, Gagne SM et al. Insights into the mechanism of heterodimerization from the 1H-NMR solution structure of the c-Myc-Max heterodimeric leucine zipper. J Mol Biol 1998; 281:165–181.PubMedGoogle Scholar
  109. 110.
    Mao DY, Watson JD, Yan PS et al. Analysis of Myc bound loci identified by CpG island arrays shows that Max is essential for Myc-dependent repression. Curr Biol 2003; 13:882–886.PubMedGoogle Scholar
  110. 111.
    Wang YH, Liu S, Zhang G et al. Knockdown of c-Myc expression by RNAi inhibits MCF-7 breast tumor cells growth in vitro and in vivo. Breast Cancer Res 2005; 7:R220–R228.PubMedGoogle Scholar
  111. 112.
    Balaji KC, Koul H, Mitra S et al. Antiproliferative effects of c-myc antisense oligonucleotide in prostate cancer cells: a novel therapy in prostate cancer. Urology 1997; 50:1007–1015.PubMedGoogle Scholar
  112. 113.
    Siddiqui-Jain A, Grand CL, Bearss DJ et al. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci USA 2002; 99:11593–11598.PubMedGoogle Scholar
  113. 114.
    Mo H, Henriksson M. Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation. Proc Natl Acad Sci USA 2006; 103:6344–6349.PubMedGoogle Scholar
  114. 115.
    Claasen G, Brin E, Crogan-Grundy C et al. Selective activation of apoptosis by a novel set of 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-quinolinones through a Myc-dependent pathway. Cancer Lett 2008; 274:243–249.Google Scholar
  115. 116.
    Giorello L, Clerico L, Pescarolo MP et al. Inhibition of cancer cell growth and c-Myc transcriptional activity by a c-Myc helix 1-type peptide fused to an internalization sequence. Cancer Res 1998; 58:3654–3659.PubMedGoogle Scholar
  116. 117.
    Berg T, Cohen SB, Desharnais J et al. Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts. Proc Nat Acad Sci USA 2002; 99:3830–3835.PubMedGoogle Scholar
  117. 118.
    Xu Y, Shi J, Yamamoto N et al. A credit-card library approach for disrupting protein-protein interactions. Bioorg Med Chem 2006; 14:2660–2673.PubMedGoogle Scholar
  118. 119.
    Kiessling A, Wiesinger R, Sperl B et al. Selective inhibition of c-Myc/Max dimerization by a pyrazolo[1,5-a] pyrimidine. ChemMedChem 2007; 2:627–630.PubMedGoogle Scholar
  119. 120.
    Prochownik EV. c-Myc as a therapeutic target in cancer. Expert Rev Anticanc 2004; 4:289–302.Google Scholar
  120. 121.
    Ponzielli R, Katz S, Barsyte-Lovejoy D et al. Cancer therapeutics: targeting the dark side of Myc. Eur J Cancer 2005; 41:2485–2501.PubMedGoogle Scholar
  121. 122.
    Soucek L, Whitfield J, Martins CP et al. Modelling Myc inhibition as a cancer therapy. Nature 2008; 455:679–683.PubMedGoogle Scholar
  122. 123.
    Soucek L, Helmer-Citterich M, Sacco A et al. Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene 1998; 17:2463–2472.PubMedGoogle Scholar
  123. 124.
    Iakoucheva LM, Brown CJ, Lawson JD et al. Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 2002; 323:573–584.PubMedGoogle Scholar
  124. 125.
    Wang H, Hammoudeh DI, Follis AV et al. Improved low molecular weight Myc-Max inhibitors. Mol Cancer Ther 2007; 6:2399–2408.PubMedGoogle Scholar
  125. 126.
    Mustata G, Follis AV, Hammoudeh DI et al. Discovery of novel myc-max heterodimer disruptors with a 3-dimensional pharmacophore model. J Med Chem 2009; 52:1247–1250.PubMedGoogle Scholar
  126. 127.
    Uversky VN, Gillespie JR, Fink AL. Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 2000; 41:415–427.PubMedGoogle Scholar
  127. 128.
    Uversky VN, Oldfield CJ, Dunker AK. Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 2005; 18:343–384.PubMedGoogle Scholar
  128. 129.
    Mittag T, Orlicky S, Choy WY et al. Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor. Proc Natl Acad Sci USA 2008; 105:17772–17777.PubMedGoogle Scholar
  129. 130.
    Mittag T, Kay LE, Forman-Kay JD. Protein dynamics and conformational disorder in molecular recognition. J Mol Recognit 2010; 23:105–116.PubMedGoogle Scholar

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© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Ariele Viacava Follis
    • 1
  • Charles A. Galea
    • 2
  • Richard W. Kriwacki
    • 1
    • 3
    Email author
  1. 1.Department of Structural BiologySt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Structural Biology DivisionWalter and Eliza Hall Institute of Medical ResearchParkvilleAustralia
  3. 3.Department of Molecular SciencesUniversity of Tennessee Health Sciences CenterMemphisUSA

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