GENES: STRUCTURE AND REGULATION
Alternative Core Promoters Regulate Tissue-specific Transcription from the Autoimmune Diabetes-related ICA1 (ICA69) Gene Locus*

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Islet cell autoantigen 69-kDa (ICA69), protein product of the human ICA1 gene, is one target of the immune processes defining the pathogenesis of Type 1 diabetes. We have characterized the genomic structure and functional promoters within the 5′-regulatory region of ICA1. 5′-RNA ligase-mediated rapid amplification of cDNA ends evaluation ofICA1 transcripts expressed in human islets, testis, heart, and cultured neuroblastoma cells reveals that three 5′-untranslated region exons are variably expressed from the ICA1 gene in a tissue-specific manner. Surrounding the transcription initiation sites are motifs characteristic of non-TATA, non-CAAT, GC-rich promoters, including consensus Sp1/GC boxes, an initiator element, cAMP-responsive element-binding protein (CREB) sites, and clusters of other putative transcription factor sites within a genomic CpG island. Luciferase reporter constructs demonstrate that the first two ICA1exon promoters reciprocally stimulate luciferase expression within islet- (RIN 1046-38 cells) and brain-derived (NMB7) cells in culture; the exon A promoter exhibits greater activity in islet cells, whereas the exon B promoter more efficiently activates transcription in neuronal cells. Mutation of a CREB site within the ICA1exon B promoter significantly enhances transcriptional activity in both cell lines. Our basic understanding of expression from the functional core promoter elements of ICA1 is an important advance that will not only add to our knowledge of the ICA69 autoantigen but will also facilitate a rational approach to discover the function of ICA69 and to identify relevant ICA1 promoter polymorphisms and their potential associations with disease.

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Published, JBC Papers in Press, October 29, 2002, DOI 10.1074/jbc.M210175200

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This work was supported by the University of Pittsburgh M.D.,Ph.D. Program (to R. P. F.), the Henry Hillman Endowment Chair in Pediatric Immunology (to M. T.), National Institutes of Health Grants R01 DK53456 and R01 DK56200 (to M. P.), and an American Diabetes Association Career Development award (to M. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EBI Data Bank with accession number(s) , , , BAC503D2, , , YAC813G2, , YAC813G2, and.

Present address: Medical Services-GRB 740, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114-2696.