The overall aim of this Phase I proposal is to devise therapeutic modalities which will assure constitutive expression of antigenic proteins needed for effective cell-mediated immunity against the tumor cells. These studies will focus on the regulation of genes that modulate the expression of the melanocyte lineage antigen, Melan-A/MART-1. We shall elucidate the mechanisms by which recently characterized tumor-produced cytokines effect """"""""antigen silencing."""""""" We shall perform a detailed analysis of mechanisms for transcriptional control of Melan-A/MART-1 as a means to overcome suppression of Melan-A/MART-l expression. Candidate transcription factors will be tested to determine if they bind to the Melan-A/MART-1 promoter. Occupancy of the Melan-A/MART-1 promoter will also be assessed by DNA footprinting. A series of Melan-A/MART-1 promoter reporter constructs will be used to analyze putative transcriptional repression sites in the promoter region. These studies will compare Melan-A/MART-1 positive and negative tumor cell variants, as well as assess the effects of antigen-silencing cytokines on mRNA transcripts and promoter occupancy. The results of this Phase I project will allow us to devise strategies for enhancement of Melan-A/MART-1 expression to overcome """"""""antigen-silencing.""""""""
| Haggerty, Timothy J; Dunn, Ian S; Rose, Lenora B et al. (2012) A screening assay to identify agents that enhance T-cell recognition of human melanomas. Assay Drug Dev Technol 10:187-201 |
| Haggerty, Timothy J; Dunn, Ian S; Rose, Lenora B et al. (2011) Topoisomerase inhibitors modulate expression of melanocytic antigens and enhance T cell recognition of tumor cells. Cancer Immunol Immunother 60:133-44 |
| Dunn, Ian S; Haggerty, Timothy J; Kono, Michihiro et al. (2007) Enhancement of human melanoma antigen expression by IFN-beta. J Immunol 179:2134-42 |
| Kono, Michihiro; Dunn, Ian S; Durda, Paul J et al. (2006) Role of the mitogen-activated protein kinase signaling pathway in the regulation of human melanocytic antigen expression. Mol Cancer Res 4:779-92 |
