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BETTE KORBER for the Degree of Doctor of Philosophy Chemical

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BETTE KORBER for the Degree of Doctor of Philosophy Chemical REGULATION OF GLASS I GENES BY INTERFERONS Thesis by BETTE KORBER In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Division of Chemistry and Chemical Engineering California Institute of Technology Pasadena, California 1988 (submitted May 17, 1988) 11 This thesis is dedicated to my shelter and my storm, James Theiler. Ill Through the years, a man peoples a space with images of provinces, kingdoms, mountains, bays, ships, islands, fishes, rooms, tools, stars, horses, and people. Shortly before his death, he discovers that the patient labyrinth of lines traces the image of his own face. Beyond my anxiety, beyond this writing, the universe waits, inexhaustible, inviting. — Jorge Luis Borges You see, one thing is, I can live with doubt and uncertainty and not knowing. I think it is much more interesting to live not knowing than to have answers which might be wrong. I have approximate answers and possible beliefs and different degrees of certainty about different things... I don’t feel frightened by not knowing things, by being lost in a mysterious universe without having any purpose, which is the way it really is, so far as I can tell... I don’t feel frightened. — Richard P. Feynman Don’t be blue, be determined. — Leroy Hood iV TABLE OF COHTEHTS Page Acknowledgements...........................................................................................................................................................'v Abstract................................................................................................................................................................................ vil Chapter One Introduction.............................................................................................................................................................. 1 Chapter T⅛o The regulation of murine class I genes by interferons is controlled by regions located both 5’ and 3, to the transcription initiation site.......................................................................................................................................................................................21 Chapter Three Regulation of gene expression by interferons: control of H-2 promoter responses............... .. ...................................................................... .............................................. .. .48 Chapter Four Regulatory elements in the promoter of the H-2D^ class I gene............... 91 Chapter Five Conclusions................................................................................................................................................................103 Chapter Six Procedures...................................................................................................................................................................Ill V ACK1VOV7LSBG^ME39TS With many thanks to: — my first and finest teachers, George, Gladys and Dorothy Korber, — my expert and generous guides through the labyrinths of scientific thought, Lee Hood and Iwona Stroynowski, — Norman Davidson and Ray Owen, for providing wings to be under, — Marie Kremρin and Kay Blackburn for excellent assistance with tissue culture and for being wonderful human beings, — Roger Perlmutter and Mr. Ohshima, for being catalysts, — the professors who were generous both with their abundant knowledge and with their less than abundant time, in particular Ellen Rothenberg and my committee members, — the people whose friendship has taught me about life and biology, and who have by their example made clear that the two are not incompatible: Joanne Topol, Ulf Landegren, Stu Scherer, Fedora Sutton, Laura Hoops, Dave and Maggie Price, Gerry Siu, Sasha Kamb, Raul Saavedra, and Sue Rosenberg, — the splendid people who have made Braun a building worth entering despite its paucity of windows: Keith Lewis, Warren Kibbe, Joe Minor, Terry Koch, Kathleen Segesman, Bertha Jones, Ria de Bruyn, Jesse Walker, Tim Hunkapillar, Joan Goverman, Debbie Nickerson, and Elly de Pagter, to name a few. VI — Saint Brian Warr, with a reminder that it takes three quivering strings to make a chord, — Keith Lewis, for help with two-dimensional gels, a constant supply of monoclonal antibodies, and all around good sense, — Warren Kibbe, David Price, and Carl Parker for advice about nuclear extracts and chromatography, — Mark Muldoon, for help with statistical analysis, — the friends who from outside looked in most closely and shared their wisdom, love, and reason: James Theiler, Kazu Akimoto, Michael Kovari, Mark Muldoon, Andy Black, Lisa Novick, Chi-Bin Chien, Shelley Stark, David Stone, Jackie Hammond, and Shelley Cotrell, — the Biology Division typing pool and graphic arts, for their patience and fine work, — the NIH and Caltech for support and a home, — James Theiler, Elly de Pagter, and Iwona Stroynowski, for help with this thesis, — and mammals, for participating in the evolution of such elegant ways to "know thyself" at a cellular and molecular level. V1X Abstract Major histocompatibility (MHC) class I gene expression is increased in response to interferons. In order to identify critical regulatory regions in mouse MHC (H-2) class I genes, the 5’ flanking region and the DNA downstream of the transcription initiation site were analyzed separately. The promoters of H-2D^ and H-2L^ were linked to the reporter gene chloramphenicol acetyl transferase (CAT). Conversely, the H-2Lc^ structural gene was linked to non-interferon regulated promoters. These constructs were transfected into several different cell lines, and their ability to respond to interferons was assessed. Both regions, 5, and 3’ of the transcriptional initiation site, were able to independently contribute to the regulation of class I genes by interferons. The basal levels of expression, interferon inducibility, and the relative contributions of the 3* and 5, responses to overall interferon regulation, were cell-type dependent. Sequence analysis of the 5, flanking region of class I genes led to the identification of multiple DNA motifs that are highly homologous to regulatory elements found in other genes. The H-2D^ promoter contains a TATA box, CAAT elements, enhancer regions, and an interferon consensus sequence that is found in the promoters of many genes that are regulated by interferons. Deletion analysis and expression studies of the H-2D^ promoter revealed several interesting regulatory features of the interferon consensus sequence. It was required for both type I (alpha and beta) and type II interferon (gamma) responses. In some cell types an additional sequence was required for a type I interferon response; this sequence is located 5, and adjacent to the interferon consensus Vlll sequence. Type II interferon action was independent of this upstream sequence in all cell-types tested. Therefore the promoter controlled response to interferons is complex, and the nature of the response depends both on the type of interferon and the cell-type being tested. He have noted that ap interferon consensus sequence homology exists in the promoters of interferon genes. As interferons have a capacity to be auto-regulatory, we propose a model of gene regulation by interferons that incorporates what our studies and others have shown about the regulation of class I genes by interferon, and what is known about the regulation of interferon genes themselves. 1 CHAPTER ONE INTRODUCTION 2 Introduction This thesis concerns the regulation by interferon of H-2 class I molecules. This is a biologically relevant issue because the interferon induction of class I molecules may have bearing on the success with which an organism mounts an immune response, by enhancing the antigen- specific lytic effect of cytotoxic T cellä. This problem is interesting from other perspectives as well. Better understanding of how interferons regulate genes can be fit into the emerging picture of how eukaryotic genes are regulated in general. Also, defining the mechanisms interferons use to regulate immunologically relevant genes may eventually have application for designing therapies that can stimulate or repress different specific aspects of a cellular response to tumors or viral infections. This introduction describes the structure, function, and expression patterns of major histocompatibility complex (MHC) class I antigens, provides a brief summary of relevant aspects of the role of interferons in the immune response, and describes how the regulatory elements of class I genes can be interpreted in the context of current general models of gene regulation. The ensuing chapters are arranged so that a published paper begins each chapter, followed by an appendix that describes additional experiments that pertain to the major topic of the chapter, and/or a discussion of pertinent data recently published from other laboratories. Structure and Function of Major Histocompatibility Antigens H-2 class I molecules are polymorphic membrane-bound glycoproteins 3 that function as recognition molecules in cell mediated immune reactions (1,2). Their primary physiological role is to present viral or tumor antigens to cytotoxic T lymphocytes. A T cell receptor recognizes antigen in association with a particular MHC class I (or class II, discussed below) molecule (2). This MHC protein mediated restriction of pathogenic antigens is critical for distinguishing self from non-self and for the elimination of diseased cells from their host. Class I molecules are composed of two polypeptide chains.
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