INSULIN EXPRESSION IN PANCREATIC-ISLET CELLS RELIES ON COOPERATIVE INTERACTIONS BETWEEN THE HELIX-LOOP-HELIX FACTOR E47 AND THE HOMEOBOX FACTOR STF-1

The development of endocrine cell types within the pancreas is thought to involve the progressive restriction of pluripotential stem cells, which gives rise to the four major cell types: insulin-, glucagon-, so matostatin-, and pancreatic polypeptide-expressing cells. The mechanis m by which these peptide hormone genes are induced and then either mai ntained or repressed during development is unknown, but their coexpres sion in early precursor cells suggests the involvement of common regul atory factors. Here we show that the somatostatin transcription factor STF-1 is also a principal regulator of insulin expression in beta-cel ls of the pancreas. STF-1 stimulates the insulin gene by recognizing t wo well defined islet-specifying elements on the insulin promoter and by subsequently synergizing in trans with the juxtaposed helix-loop-he lix protein E47. Within the STF-1 protein, an N-terminal trans-activat ion domain functions cooperatively with E47 to stimulate insulin trans cription. As truncated STF-1 polypeptides lacking the N-terminal activ ation domain strongly inhibit insulin promoter activity in beta-islet cells, our results suggest that the specification of islet cell types during development may be in part determined by the expression of STF- 1 relative to other islet cell factors.