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TWO NOVEL MECHANISMS of MHC CLASS I DOWN- REGULATION in HUMAN CANCER: ACCELERATED DEGRADATION of TAP-1 Mrna and DISRUPTION of TAP-1 PROTEIN FUNCTION

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TWO NOVEL MECHANISMS of MHC CLASS I DOWN- REGULATION in HUMAN CANCER: ACCELERATED DEGRADATION of TAP-1 Mrna and DISRUPTION of TAP-1 PROTEIN FUNCTION TWO NOVEL MECHANISMS OF MHC CLASS I DOWN- REGULATION IN HUMAN CANCER: ACCELERATED DEGRADATION OF TAP-1 mRNA AND DISRUPTION OF TAP-1 PROTEIN FUNCTION DISSERTATION Presented in Partial Fulfillment of the Requirement for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University by Tianyu Yang * * * * * The Ohio State University 2004 Dissertation Committee: Approved by Professor Pan Zheng, Adviser Professor Yang Liu Professor Joan Durbin Professor Xuefeng Bai Adviser Department of Pathology Professor William Lafuse ABSTRACT Both viruses and tumors evade cytotoxic T lymphocyte (CTL)-mediated host immunity by down-regulation of major histocompatibility complex (MHC) class I antigen presentation machinery. The transporter associated with antigen processing (TAP), a heterodimer of TAP-1 and TAP-2, plays essential role in the MHC class I- restricted antigen presentation pathway by translocating antigenic peptides from cytosol into the ER lumen, where the assembly of MHC class I complex takes place. TAP deficiency is a frequent observation in human cancers, which is one of the causes of MHC class I down-regulation. However, the underlying molecular mechanism has been limited. In search for novel mechanisms of TAP deficiency and MHC class I down- regulation in human cancer cells, we characterized an MHC class I-deficient melanoma cell line SK-MEL-19. The expression of TAP-1 mRNA was found deficient in this cell line even after interferon-gamma (IFN-γ) stimulation, despite its active transcription. This abnormality is caused by a single nucleotide deletion at position +1489 of the TAP- 1 gene, which results in rapid degradation of the TAP-1 mRNA. Subsequently, using this TAP-1 deficient cell line, we studied the function of TAP-1 variants containing amino acid changes within or close to the signature motif that exist in the normal population or were generated by site-directed mutagenesis. All the TAP-1 variants showed decreased ii function compared to the wild type, which supports an essential role of the signature motif in TAP transporter function. One of these variants, TAP-1 R648Q, with the alteration immediately C-terminal to the signature motif, was found to occur 17.5 times more frequently in HLA- colon cancers than those with normal HLA levels. Functional analysis revealed that the Q648 variant retained only about 20% peptide translocation activity compared to TAP-1 (R648). To our knowledge, the two mechanisms we identified in this work, which lead to abrogation of TAP-1 expression and decreased TAP transporter function, respectively, have not been addressed before. The determination of transporter activity of a natural TAP-1 variant, TAP-1 R648Q, and its increased presence in HLA- colon cancer samples may help to develop diagnostic and therapeutic methods for colon cancer immunotherapy. iii DEDICATION Dedicated to my parents. iv ACKNOWLEDGMENTS I wish to thank my adviser, Dr. Pan Zheng for her support and encouragement, and for her patience in correcting my stylistic and scientific errors. I thank Dr. Yang Liu for his valuable advice. Without them, this thesis would not be possible. I thank Philip E. Lapinski and Haotian Zhao for their contribution to this work. I’m in debted to Dr. Soledad Fernandez for the statistical analysis and Dr. Qunmin Zhou for sharing normal population blood DNA samples. I thank Dr. Jian-Xin Gao, Dr. Huiming Zhang, Dr. Kurtis Yearsley and Paul Rangel for technical assistance. I am grateful to Dr. Soldano Ferrone for providing us the SK-MEL-19 cell line, Dr. Malini Raghavan for providing the peptide and technical assistance for the peptide translocation assay and Dr. Peter Cresswell for rabbit antiserum against TAP1 and tapasin. This work was supported by NIH grants CA82355, CA58033 and CA69091, Department of Defense grant DAMD17-00-1-0041 and the Ohio State University Comprehensive Cancer Center. v VITA November 8, 1974 ………………………Born, Hebei, People’s Republic of China 1998 ……………………………………..Bachelor in Medicine and Master in Medicine, China medical University 1998 - present ……………………………Graduate Research Assistant, The Ohio State University PUBLICATIONS Research Publication 1. T. Yang, B.A. McNally, S. Ferrone, Y. Liu, and P. Zheng, “A single-nucleotide deletion leads to rapid degradation of TAP-1 mRNA in a melanoma cell line”. J Biol Chem, 278(17), 15291-6, (2003). 2. Y. Guo, T. Yang, X. Liu, S. Lu, J. Wen, J.E. Durbin, Y. Liu, and P. Zheng, “Cis elements for transporter associated with antigen-processing-2 transcription: two new promoters and an essential role of the IFN response factor binding element in IFN- gamma-mediated activation of the transcription initiator”. Int Immunol, 14(2), 189-200, (2002). FIELDS OF STUDY Major Field: Immunology. vi TABLE OF CONTENTS Page ABSTRACT................................................................................................................................................... ii DEDICATION ...............................................................................................................................................iv ACKNOWLEDGMENTS...............................................................................................................................v VITA ..............................................................................................................................................................vi LIST OF TABLES .........................................................................................................................................ix LIST OF FIGURES.........................................................................................................................................x 1. INTRODUCTION ............................................................................................................................1 1.1 Major histocompatibility complex (MHC) class I-restricted antigen processing and presentation.......................................................................................................................................1 1.2 Presentation of exogenous antigens by the class I MHC molecules. ..........................................7 1.3 TAP-1 gene expression and protein function,...........................................................................11 1.4 Impaired MHC Class I expression in viral infection.................................................................16 1.5 MHC Class I down-regulation in cancer...................................................................................18 2. MATERIALS AND METHODS....................................................................................................30 2.1 Cell lines ...................................................................................................................................30 2.2 Antibodies.................................................................................................................................30 2.3 Flow cytometry .........................................................................................................................31 2.4 Northern blot.............................................................................................................................31 2.5 Southern blot.............................................................................................................................32 2.6 Generation of TAP-1 cDNA constructs and stable transfection................................................32 2.7 Generation of TAP-1 constructs and Tet-Off SK-MEL-19 cell lines for RNA stability analyses ........................................................................................................................................................34 2.8 Generation of luciferase reporter constructs and assay for promoter activity ...........................34 2.9 Nuclear run-on assay.................................................................................................................35 2.10 Restriction fragment length polymorphism (RFLP)................................................................36 2.11 RNase protection assay ...........................................................................................................36 2.12 Immunofluorescence microscopy ...........................................................................................37 2.13 Immunoprecipitation...............................................................................................................38 2.14 Microsome-based peptide translocation assay ........................................................................39 2.15 Colon cancer tissue sections, immunohistochemistry and statistical analysis.........................40 2.16 Isolation of genomic DNA and genotyping ............................................................................41 3. A SINGLE-NUCLEOTIDE DELETION LEADS TO RAPID DEGRADATION OF TAP-1 MRNA IN A MELANOMA CELL LINE ......................................................................................42 3.1 Introduction...............................................................................................................................42 3.2 Results and discussion. .............................................................................................................44 3.2.1 Down-regulation of TAP-1 mRNA by a posttranscriptional mechanism in melanoma cell line SK-MEL-19 ...........................................................................................................44
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