Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1.

The BTB/POZ transcriptional repressor HIC1 (Hypermethylated in Cancer 1) is a tumor suppressor gene located at chromosome 17p13.3, a region frequently hypermethylated or deleted in human tumors and in a contiguous-gene syndrome, the Miller-Dieker syndrome. The human and murine HIC1 genes are composed of two alternative 5' exons, 1a and 1b fused to a large second coding exon 2. Exon 1a is a noncoding exon associated with a major G-C-rich promoter whereas exon 1b is a downstream coding exon associated with a minor TATA box promoter. By human-mouse genome comparison, we have identified a short upstream conserved sequence containing G-C boxes which were shown to be functional. Transcripts initiating from this new promoter were detected in various human and mouse tissues and contained a long 5'-UTR sequence, called 1c which encompass the G-C-rich promoter associated with exon 1a and uses the same splice donor site. RT-PCR analyses of two primary breast epithelial cell lines identified two other 5'-UTRs generated by alternative splicing within exon 1c. Our results thus highlight the existence of an unexpected complex transcriptional regulation of HIC1.