Human leukocyte antigen (HLA)-A, B and C class I molecules are expressed on the surface of almost all nucleated cells and present endogenously processed peptide antigen to cytotoxic T lymphocytes. This process forms the basis by which the immune system eliminates virally infected or malignantly transformed cells. HLA-A and B proteins have well characterized structure and function, but HLA-C proteins are poorly characterized. Protein products of the HLA-C class I genes are expressed at low levels and this has been shown to correlate to low HLA-C mRNA abundance caused by rapid mRNA turnover. The protein products of several gene families, including cytokines and oncogenes, are deleterious to the host when over-expressed. These genes maintain low protein expression by destabilizing mRNA. HLA-C MRNA has a half-life similar to cytokine and oncogene genes. These data suggest that over-expression of HLA-C protein products may be discerned by understanding the mRNA regulatory mechanisms.
The specific aims described in this proposal are to determine how cis and trans acting elements regulate HLA-C mRNA stability, and identify locus specific nucleic acid residues that form a regulatory element. Cis acting elements will be detected by generating chimeric reporter plasmid constructs, HLA-B/C genes, site directed mutants and RNase H analysis. Trans acting elements will be assessed using gel mobility shift assays and reporter constructs to test the role for translation. A database of HLA-B and C nucleic acid sequences will be generated to determine locus specific nucleic acid residues; appropriate sequences will be compared to other genes. The immediate goal of these studies is to determine mechanisms associated with HLA mRNA regulation. The long range goals of these studies will be to determine the biological significance of low HLA-C cell surface expression and examine the effects of alteration of HLA-C surface expression levels. These studies will increase our understanding of immune regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI039029-03
Application #
2672642
Study Section
Special Emphasis Panel (ZRG2-ALY (01))
Project Start
1996-08-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
New York University
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Chesler, David A; McCutcheon, Jane A; Reiss, Carol Shoshkes (2004) Posttranscriptional regulation of neuronal nitric oxide synthase expression by IFN-gamma. J Interferon Cytokine Res 24:141-9
Fine, Craig I; Han, C David; Sun, Xuming et al. (2002) Tobacco reduces membrane HLA class I that is restored by transfection with transporter associated with antigen processing 1 cDNA. J Immunol 169:6012-9