TISSUE-SPECIFIC EXPRESSION OF HUMAN ACHAETE-SCUTE HOMOLOG-1 IN NEUROENDOCRINE TUMORS - TRANSCRIPTIONAL REGULATION BY DUAL INHIBITORY REGIONS

Malignancies with neuroendocrine (NE) features such as medullary thyro id cancer (MTC) and small cell lung cancer (SCLC) are prototypic neopl asms arising from peripheral endocrine cells. The mechanisms that regu late the NE phenotype in these tumors and their cellular precursors ar e not well understood. However, a basic helix-loop-helix transcription factor that is homologous to Drosophila neural fate determination pro teins may have a central role. Human achaete-scute homologue-1 (hASH1) , a human homologue of the Drosophila achaete-scute complex, is highly expressed in MTC, SCLC, and pheochromocytomas, To determine what mech anisms allow constitutive expression of hASH1 in NE tumors, we cloned human genomic DNA fragments containing the hASH1 gene and characterize d its promoter region. We show that hASH1 expression is restricted to NE cell lines by a transcriptionally regulated mechanism. Dual promote rs initiate hASH1 transcription, with the predominant site being an ev olutionarily conserved initiator (INR) element. Transient transfection studies provide evidence for a generalized enhancer region that has h igh activity in all cell lines tested, Restriction of hASH1 expression to NE tumor cells depends on two tissue-specific repressor regions, p resent in the proximal and distal (>13.5 kb) 5'-flanking region, Under standing the mechanisms of tissue-specific control of hASH1 gene expre ssion provides a useful model to explore regulatory cascades influenci ng both normal nervous system development and the NE phenotype of tumo rs such as MTC and SCLC.