Photo of Nicholas J. Dyson,  PhD

Nicholas J. Dyson, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-9888
Fax: (617) 726-7808


dyson@helix.mgh.harvard.edu

Nicholas J. Dyson, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School
  • Member, MGH Cancer Center, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

We study the functions of the E2F transcription factor and retinoblastoma (RB) family of proteins, two groups of proteins that are important regulators of cell proliferation. During G1 to S phase progression, the activation of cyclin dependent kinases in G1 leads to the phosphorylation of RB-family proteins (pRB, p107 and p130), and the activation of the E2F-dependent transcription. E2F co-ordinates the expression of a set of genes that encode proteins that are essential for DNA synthesis. This series of events is tightly controlled in normal cells but is deregulated in most, if not all, tumor cells. Viral oncoproteins such as Adenovirus E1A, SV40 large T antigen and E7 proteins of human papillomaviruses have evolved to target RB-family proteins and the viruses exploit these interactions to drive quiescent cells into the cell cycle.

We use a combination of genetic and biochemical approaches to study E2F and RB-family proteins. A major goal is to identify the individual functions of RB-family proteins in the regulation of E2F activity. Because the overexpression of closely related family members often leads to a loss of specificity, our recent efforts have concentrated on loss-of-function approaches. Using primary cells from knockout mice that lack various family members, we have identified E2F-target genes that require either pRB or p107/p130 for their normal patterns of expression and have begun to identify elements of cell cycle control that depend on either pRB, p107 or p130.

To investigate the pathways that converge on E2F and the RB-family we have identified and characterized homologs of E2F (dE2F, dDP) and the RB-family (RBF) in Drosophila. We found that the Drosophila proteins control cell proliferation in ways that are directly analogous to their mammalian counterparts. We have two major goals that exploit the advantages of Drosophila. First, in order to identify the pathways that interact with E2F and RBF, we have set up genetic screens for mutations that modify dE2F/dDP- and RBF-dependent phenotypes. These phenotypes have been generated in transgenic lines by elevating the expression of dE2F, dDP and RBF specifically in the eye. Second, we are characterizing the phenotypes of mutant alleles of dE2F and RBF. Not surprisingly, these mutants have phenotypes that are far more severe than mutations of individual E2F or RB-family members in mice, and are likely to give insight into the general roles of these groups of proteins.

Publications

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  • Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 2015. PubMed
  • Miles WO, Korenjak M, Griffiths LM, Dyer MA, Provero P, Dyson NJ. Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells. EMBO J 2014. PubMed
  • Korenjak M, Kwon E, Morris RT, Anderssen E, Amzallag A, Ramaswamy S, Dyson NJ. dREAM co-operates with insulator-binding proteins and regulates expression at divergently paired genes. Nucleic Acids Res 2014. PubMed
  • Heilmann AM, Perera RM, Ecker V, Nicolay BN, Bardeesy N, Benes CH, Dyson NJ. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res 2014; 74:3947-58. PubMed
  • Manning AL, Yazinski SA, Nicolay B, Bryll A, Zou L, Dyson NJ. Suppression of genome instability in pRB-deficient cells by enhancement of chromosome cohesion. Mol Cell 2014; 53:993-1004. PubMed
  • Evertts AG, Manning AL, Wang X, Dyson NJ, Garcia BA, Coller HA. H4K20 methylation regulates quiescence and chromatin compaction. Mol Biol Cell 2013; 24:3025-37. PubMed
  • Black JC, Manning AL, Van Rechem C, Kim J, Ladd B, Cho J, Pineda CM, Murphy N, Daniels DL, Montagna C, Lewis PW, Glass K, Allis CD, Dyson NJ, Getz G, Whetstine JR. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell 2013; 154:541-55. PubMed
  • Nicolay BN, Gameiro PA, Tschöp K, Korenjak M, Heilmann AM, Asara JM, Stephanopoulos G, Iliopoulos O, Dyson NJ. Loss of RBF1 changes glutamine catabolism. Genes Dev 2013; 27:182-96. PubMed
  • Ji JY, Miles WO, Korenjak M, Zheng Y, Dyson NJ. In vivo regulation of E2F1 by Polycomb group genes in Drosophila. 2012; 2:1651-60. PubMed
  • Herr A, Longworth M, Ji JY, Korenjak M, Macalpine DM, Dyson NJ. Identification of E2F target genes that are rate limiting for dE2F1-dependent cell proliferation. Dev Dyn 2012; 241:1695-707. PubMed
  • Korenjak M, Anderssen E, Ramaswamy S, Whetstine JR, Dyson NJ. RBF Binding to both Canonical E2F Targets and Noncanonical Targets Depends on Functional dE2F/dDP Complexes. Mol Cell Biol 2012; 32:4375-87. PubMed
  • Nicolay BN, Dyson NJ. It's all in the timing: too much E2F is a bad thing. PLoS Genet. 2012; 8:e1002909. PubMed
  • Heilmann AM, Dyson NJ. Phosphorylation puts the pRb tumor suppressor into shape. Genes Dev 2012; 26:1128-30. PubMed
  • Di Stefano L, Walker JA, Burgio G, Corona DF, Mulligan P, Näär AM, Dyson NJ. Functional antagonism between histone H3K4 demethylases in vivo. Genes Dev 2011; 25:17-28. PubMed
  • Black JC, Allen A, Van Rechem C, Forbes E, Longworth M, Tschöp K, Rinehart C, Quiton J, Walsh R, Smallwood A, Dyson NJ, Whetstine JR. Conserved antagonism between JMJD2A/KDM4A and HP1粒 during cell cycle progression. Mol Cell 2010; 40:736-48. PubMed
  • Centore RC, Havens CG, Manning AL, Li JM, Flynn RL, Tse A, Jin J, Dyson NJ, Walter JC, Zou L. CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Mol Cell 2010; 40:22-33. PubMed
  • Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ, Israelian K, Westphal CH, Rodgers JT, Shioda T, Elson SL, Mulligan P, Najafi-Shoushtari H, Black JC, Thakur JK, Kadyk LC, Whetstine JR, Mostoslavsky R, Puigserver P, Li X, Dyson NJ, Hart AC, Näär AM. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev 2010; 24:1403-17. PubMed
  • Manning AL, Longworth MS, Dyson NJ. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev 2010; 24:1364-76. PubMed
  • Longworth MS, Dyson NJ. pRb, a local chromatin organizer with global possibilities. Chromosoma 2010; 119:1-11. PubMed
  • Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 2009; 11:1444-50. PubMed
  • Morris EJ,Ji JY,Yang F,Di Stefano L,Herr A,Moon NS,Kwon EJ,Haigis KM,Naar AM,Dyson NJ. E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 2008; 455:552-6. PubMed
  • van den Heuvel S,Dyson NJ. Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 2008; 9:713-24. PubMed
  • Longworth MS, Herr A, Ji JY, Dyson NJ. RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes Dev 2008; 22:1011-24. PubMed
  • Wu X, Yamada-Mabuchi M, Morris EJ, Tanwar PS, Dobens L, Gluderer S, Khan S, Cao J, Stocker H, Hafen E, Dyson NJ, Raftery LA. The Drosophila homolog of human tumor suppressor TSC-22 promotes cellular growth, proliferation, and survival. Proc Natl Acad Sci U S A 2008; 105:5414-9. PubMed
  • Moon NS,Di Stefano L,Morris EJ,Patel R,White K,Dyson NJ. E2F and p53 induce apoptosis independently during Drosophila development but intersect in the context of DNA damage. PLoS Genet 2008; 4:e1000153. PubMed
  • Moon NS, Dyson N. E2F7 and E2F8 keep the E2F family in balance. Dev Cell 2008; 14:1-3. PubMed
  • Isaac CE, Francis SM, Martens AL, Julian LM, Seifried LA, Erdmann N, Binn. The retinoblastoma protein regulates pericentric heterochromatin. Mol Cell Biol 2006; 26:3659-71. PubMed
  • Moon NS, Frolov MV, Kwon EJ, Di Stefano L, Dimova DK, Morris EJ, Taylor-Harding B, White K, Dyson NJ. Drosophila E2F1 has context-specific pro- and antiapoptotic properties during development. Dev Cell 2005; 9:463-75. PubMed
  • Stevaux O, Dimova DK, Ji JY, Moon NS, Frolov MV, Dyson NJ. Retinoblastoma family 2 is required in vivo for the tissue-specific repression of dE2F2 target genes. Cell Cycle 2005; 4:1272-80. PubMed
  • Frolov MV, Moon NS, Dyson NJ. dDP is needed for normal cell proliferation. Mol Cell Biol 2005; 25:3027-39. PubMed
  • Korenjak M, Taylor-Harding B, Binn. Native E2F/RBF complexes contain Myb-interacting proteins and repress transcription of developmentally controlled E2F target genes. Cell 2004; 119:181-93. PubMed
  • Taylor-Harding B, Binn. p55, the Drosophila ortholog of RbAp46/RbAp48, is required for the repression of dE2F2/RBF-regulated genes. Mol Cell Biol 2004; 24:9124-36. PubMed
  • Dimova DK, Stevaux O, Frolov MV, Dyson NJ. Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev 2003; 17:2308-20. PubMed
  • Dick FA, Dyson N. pRB contains an E2F1-specific binding domain that allows E2F1-induced apoptosis to be regulated separately from other E2F activities. Mol Cell 2003; 12:639-49. PubMed
  • Chakravarti A, Noll E, Black PM, Finkelstein DF, Finkelstein DM, Dyson NJ, Loeffler JS. Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 2002; 20:1063-8. PubMed
  • Boulton SJ, Gartner A, Reboul J, Vaglio P, Dyson N, Hill DE, Vidal M. Combined functional genomic maps of the C. elegans DNA damage response. Science 2002; 295:127-31. PubMed
  • Chakravarti A, Loeffler JS, Dyson NJ. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 2002; 62:200-7. PubMed
  • Geng Y, Yu Q, Whoriskey W, Dick F, Tsai KY, Ford HL, Biswas DK, Pardee AB, Amati B, Jacks T, Richardson A, Dyson N, Sicinski P. Expression of cyclins E1 and E2 during mouse development and in neoplasia. Proc Natl Acad Sci U S A 2001; 98:13138-43. PubMed
  • Frolov MV, Huen DS, Stevaux O, Dimova D, Balczarek-Strang K, Elsdon M, Dyson NJ. Functional antagonism between E2F family members. Genes Dev 2001; 15:2146-60. PubMed
  • Chakravarti A, Delaney MA, Noll E, Black PM, Loeffler JS, Muzikansky A, Dyson NJ. Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin Cancer Res 2001; 7:2387-95. PubMed
  • Kennedy BK, Liu OW, Dick FA, Dyson N, Harlow E, Vidal M. Histone deacetylase-dependent transcriptional repression by pRB in yeast occurs independently of interaction through the LXCXE binding cleft. Proc Natl Acad Sci U S A 2001; 98:8720-5. PubMed
  • Dick FA, Sailhamer E, Dyson NJ. Mutagenesis of the pRB pocket reveals that cell cycle arrest functions are separable from binding to viral oncoproteins. Mol Cell Biol 2000; 20:3715-27. PubMed
  • McCaffrey J, Yamasaki L, Dyson NJ, Harlow E, Griep AE. Disruption of retinoblastoma protein family function by human papillomavirus type 16 E7 oncoprotein inhibits lens development in part through E2F-1. Mol Cell Biol 1999; 19:6458-68. PubMed
  • Pan H, Yin C, Dyson NJ, Harlow E, Yamasaki L, Van Dyke T. Key roles for E2F1 in signaling p53-dependent apoptosis and in cell division within developing tumors. Mol Cell 1998; 2:283-92. PubMed
  • Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev 1998; 12:2245-62. PubMed
  • Hurford RK, Cobrinik D, Lee MH, Dyson N. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev 1997; 11:1447-63. PubMed
  • Zukerberg LR, Benedict WF, Arnold A, Dyson N, Harlow E, Harris NL. Expression of the retinoblastoma protein in low-grade B-cell lymphoma: relationship to cyclin D1. Blood 1996; 88:268-76. PubMed
  • Yamasaki L, Jacks T, Bronson R, Goillot E, Harlow E, Dyson NJ. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 1996; 85:537-48. PubMed
  • Du W, Vidal M, Xie JE, Dyson N. RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. Genes Dev 1996; 10:1206-18. PubMed
  • Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K. The retinoblastoma protein binds to a family of E2F transcription factors. Mol Cell Biol 1993; 13:7813-25. PubMed
  • Dyson N, Guida P, M. Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins. J Virol 1992; 66:6893-902. PubMed
  • Helin K, Lees JA, Vidal M, Dyson N, Harlow E, Fattaey A. A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F. Cell 1992; 70:337-50. PubMed
  • Cao L, Faha B, Dembski M, Tsai LH, Harlow E, Dyson N. Independent binding of the retinoblastoma protein and p107 to the transcription factor E2F. Nature 1992; 355:176-9. PubMed
  • Münger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J 1989; 8:4099-105. PubMed
  • Dyson NJ, Brown TA, Ray JA, Waring RB, Scazzocchio C, Davies RW. Processing of mitochondrial RNA in Aspergillus nidulans. J Mol Biol 1989; 208:587-99. PubMed
  • Dyson N, Howley PM, Münger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989; 243:934-7. PubMed
  • Dyson NJ, Brown TA, Waring RB, Davies RW. The mitochondrial ribosomal RNA molecules of Aspergillus nidulans. Gene 1989; 75:109-18. PubMed
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