UCLA ACCESS
Arnold J. Berk, M.D.

Laboratory Address:
UCLA/MBI
611 Young Dr E
Los Angeles, CA 90095

Work Address:
Boyer 359
CAMPUS - 157005
CA

Department / Division Affiliations
Affiliations
Member, JCCC Gene Regulation Program Area
Research Interests
We study molecular interactions that regulate transcription in mammalian cells, focusing particular attention on transcription factors encoded by oncogenes and tumor suppressors and the regulation of cell replication. Since the decision to initiate transcription is the key control point regulating expression of most genes, transcriptional regulation determines the properties of both normal and abnormal cells. Many of our projects involve proteins expressed early during infection by DNA viruses because these proteins have evolved to interact with key host cell regulatory proteins in order to maximize the yield of progeny virions. Consequently, they have directed us to critical cellular regulatory proteins with which they interact, such as p53, the Retinoblastoma protein family, the mediator of transcription complex, and chromatin modifying complexes. In recent years we discovered that the adenovirus large E1A protein activates transcription from viral promoters by making a high affinity interaction with a specific subunit of the mediator of transcription complex, MED23. We found that activator-mediator interactions stimulate pre-initiation complex assembly on promoter DNA, and that these interactions also stimulate a post-recruitment step in transcription initiation responsible for the "paused polymerases" recently observed at most mammalian promoters. We also study inactivation of the p53 tumor suppressor by adenovirus E1B. Recently we discovered that repression involves sequestration of p53 in subnuclear domains called PML-nuclear bodies. This results from transient covalent attachment of SUMO1 proteins to monomers in a large molecular lattice of E1B and p53. Our recent work can explain the fascinating enigma of how all p53 molecules are inactivated when only ~1% are modified by SUMO1. Recently, we applied "ChIP on chip" methodology to discover how the adenovirus small e1a protein forces contact-inhibited human cells to proliferate: small e1a directly re-localizes major chromatin-modifying complexes on a global genomic scale. Finally, we also work in the area of gene therapy: we have engineered an adenovirus-Epstein-Barr virus hybrid vector that introduces stable episomes into infected cells in tissues of intact animals.
Publications
Pennella MA, Liu Y, Woo JL, Kim CA, and Berk AJ. Adenovirus E1B-55K is a p53-SUMO1 E3 ligase that stimulates p53 nuclear export and inhibition through interactions in PML-nuclear bodies. J. Virol 2010; in press: .
Gil JS, Gallaher SD, Berk AJ. Delivery of an EBV episome by a self-circularizing helper- dependent adenovirus: long-term transgene expression in immunocompetent mice. Gene Therapy 2010; May 13. [Epub ahead of print]: .
Balamotis MA, Pennella MA, Stevens JL, Wasylyk B, Belmont AS, Berk AJ. Complexity in Transcription Control at the Activation Domain-Mediator Interface. Science Signaling 2009; 2: ra20, 1-12.
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Sean D. Gallaher, Jose S. Gil, Oliver Dorigo, Arnold J. Berk Robust In Vivo Transduction of a Genetically Stable EBV Episome to Hepatocytes in Mouse by a Hybrid Viral Vector. J. Virol 2009; 83: 3249-3257.
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Ferrari R, Berk AJ, Kurdistani SK Viral manipulation of the host epigenome for oncogenic transformation. Nature Reviews Genetics 2009; 10: 290-294.
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Gregory A. Horwitz, Kangling Zhang, Matthew A. McBrian, Michael Grunstein, Siavash Kurdistani, and Arnold J. Berk Adenovirus small e1a alters global patterns of histone modification. Science 2008; 321: 1084-1085.
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Roberto Ferrari, Matteo Pellegrini, Gregory A. Horwitz, Wei Xie, Arnold J. Berk, and Siavash Kurdistani Epigenetic reprogramming by adenovirus e1a. Science 2008; 321: 1086-1088.
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Woo, JL, Berk AJ. Adenovirus ubiquitin-protein ligase stimulates viral late mRNA nuclear export. J. Virol. 2007; 81: 575-587. [Spotlight article].
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Schwarz J, Schwarz SC, Dorigo O, Stutzer A, Wegner F, Labarca C, Deshpande, P, Gil JS, Berk AJ, Lester HA. Enhanced Expression of L9'S Mutant nAChR in Adult Mice Increases the Loss of Midbrain Dopaminergic Neurons . FASEB Journal 2006; 20: 935-46.
Liu, Y., Shevchenko, A., Shevchenko, A., and Berk, A.J. Adenovirus exploits the cellular aggresome response to inactivate the MRN complex. J. Virol 2005; 79: 14004-16.[Spotlight article].
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Wang G, Balamotis MA, Stevens JL, Yamaguchi Y, Handa H, Berk AJ Mediator requirement for both recruitment and postrecruitment steps in transcription initiation. Molecular Cell. 2005; 17(5): 683-94.
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Berk, A. J. Recent lessons from adenovirus in gene expression, cell cycle control, and cell biology. Oncogene 2005; 21: 7673-85.
Yue, Q., Groszer M., Gil J.S., Berk, A.J., Messing A., Wu, H., Liu, X. PTEN deletion in Bergmann glia leads to premature differentiation and affects laminar organization. Development 2005; 132: 3281-3291.
Bourbon HM, Aguilera A, Ansari AZ, Asturias FJ, Berk AJ, Bjorklund S, Blackwell TK, Borggrefe T, Carey M, Carlson M, Conaway JW, Conaway RC, Emmons SW, Fondell JD, Freedman LP, Fukasawa T, Gustafsson CM, Han M, He X, Herman PK, Hinnebusch AG, Holmberg S, Holstege FC, Jaehning JA, Kim YJ, Kuras L, Leutz A, Lis JT, Meisterernest M, Naar AM, Nasmyth K, Parvin JD, Ptashne M, Reinberg D, Ronne H, Sadowski I, Sakurai H, Sipiczki M, Sternberg PW, Stillman DJ, Strich R, Struhl K, Svejstrup JQ, Tuck S, Winston F, Roeder RG, Kornberg RD A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II. Molecular cell. . 2004; 14(5): 553-7.
Dorigo O, Gil JS, Gallaher SD, Tan BT, Castro MG, Lowenstein PR, Calos MP, Berk AJ Development of a novel helper-dependent adenovirus-Epstein-Barr virus hybrid system for the stable transformation of mammalian cells. Journal of Virology . 2004; 78(12): 6556-66.
Fang L, Stevens JL, Berk AJ, Spindler KR Requirement of Sur2 for efficient replication of mouse adenovirus type 1. Journal of virology. . 2004; 78(23): 12888-900.
Schroder O, Bryant GO, Geiduschek EP, Berk AJ, Kassavetis GA A common site on TBP for transcription by RNA polymerases II and III. Embo J. 2003; 22(19): 5115-24.
Cantin GT, Stevens JL, Berk AJ Activation domain-mediator interactions promote transcription preinitiation complex assembly on promoter DNA. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100(21): 12003-8.
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Martel LS, Brown HJ, Berk AJ Evidence that TAF-TATA box-binding protein interactions are required for activated transcription in mammalian cells. Molecular and cellular biology. 2002; 22(8): 2788-98.
Stevens JL, Cantin GT, Wang G, Shevchenko A, Shevchenko A, Berk AJ Transcription control by E1A and MAP kinase pathway via Sur2 mediator subunit. Science. 2002; 296(5568): 755-8.
Wang G, Cantin GT, Stevens JL, Berk AJ Characterization of mediator complexes from HeLa cell nuclear extract. Molecular and cellular biology. . 2001; 21(14): 4604-13.
Tan BT, Wu L, Berk AJ Adeno-Epstein-Barr Virus Hybrid Vector that Stably Transforms Cultured Cells with High Efficiency. J. Virol 1999; 73: 7582-7589.
Gambhir SS, Barrio JR, Phelps ME, Iyer M, Namavari M, Satyamurthy N, Wu L, Green LA, Bauer E, MacLaren D,C Nguyen K, Berk AJ, Cherry SR, Herschman HR Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography. Proceedings of the National Academy of Sciences of the United States of America. . 1999; 96(5): 2333-8.
Boyer TG, Martin ME, Lees E, Ricciardi RP, Berk AJ Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein. Nature. . 1999; 399(6733): 276-9.
Lieberman JR, Lee LQ, Wu L, Finerman GAM, Berk A, Witte ON, Stevenson S Regional gene therapy with a BMP-2 producing murine stromal cell line induces heterotropic bone formation in rodents. Journal of Orthopedic Research 1998; 16: 330-339.
Bryant GO, Martel LS, Burley SK, Berk AJ Radical mutagenesis reveals TATA-box binding protein surfaces required for activated transcription in vivo. Genes & Development 1996; 10: 2491-2504.
Lieberman PM, Berk AJ A mechansim for TAFs in transcriptional activation: activation domain enhancement of TFIID-TFIIA-promoter DNA complex formation. Genes & Development 1994; 8: 995-1006.
Yew PR, Liu X, and Berk AJ Adenovirus E1B oncoprotein tethers a transcriptional repression domain to p53. Genes & Development 1994; 8: 190-202.
Zhou Q, Lieberman PM, Boyer TG, and Berk AJ Holo TFIID supports transcriptional stimulation by diverse activators and from a TATA-less promoter. Genes & Development 1992; 6: 1964-1974.
Yew PR, Berk AJ Inhibition of p53 transactivation required for transformation by adenovirus early 1 B protein. Nature 1992; 357: 82-85.
Kao CC, Lieberman PM, Schmidt MC, Zhou Q, Pei R, Berk AJ Cloning of a transcriptionally active human TATA binding factor. Science. . 1990; 248(4963): 1646-50.
Schmidt MC, Kao CC, Pei R, Berk AJ Yeast TATA-box transcription factor gene. Proceedings of the National Academy of Sciences USA 1989; 86: 7785-7789.
Berk AJ, Sharp PA. Spliced early messenger RNAs of simian virus 40. Proc. Natl. Acad. Sci. USA 1978; 75: 1274-1278.
Berget SM, Berk AJ, Harrison T, Sharp PA Spliced segments at the 5' termini of adenovirus 2 late mRNA: a role for heterogeneous nuclear RNA in mammalian cells. Cold Spring Harbor Symposium on Quantitative Biology 1978; 42: 523-529.
Berk AJ, Sharp PA Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of Sl endonuclease-digested hybrids. Cell 1977; 12: 721-732.