STRUCTURAL-ANALYSIS OF THE HUMAN BIN1 GENE - EVIDENCE FOR TISSUE-SPECIFIC TRANSCRIPTIONAL REGULATION AND ALTERNATE RNA SPLICING

BIN1 is a putative tumor suppressor that was identified through its in teraction with the MYC oncoprotein. To begin to identify elements of B IN1 whose alteration may contribute to malignancy, we cloned and chara cterized the human BIN1 gene and promoter, Nineteen exons were identif ied in a region of >54 kilobases, six of which were alternately splice d in a cell type-specific manner. One alternately spliced exon encodes part of the MYC-binding domain, suggesting that splicing controls the MYC-binding capacity of BIN1 polypeptides. Four other alternately spl iced exons encode amphiphysin-related sequences that were included in brain-specific BIN1 species, also termed amphiphysin isoforms or amphi physin II. The 5'-flanking region of BIN1 is GC-rich and lacks a TATA box but directs transcriptional initiation from a single site, A simil ar to 0.9-kilobase fragment from this region was sufficient for basal transcription and transactivation by MyoD, which may account for the h igh levels of BIN1. observed in skeletal muscle. This study lays the f oundation for genetic and epigenetic investigations into the role of B IN1 in normal and neoplastic cell regulation.