Polypeptide Hormone Gene Regulation 
DNA-binding proteins and with adjacent target 
DNA sequences appear to determine cellular 
specificity of gene expression as well as metaboli- 
cally regulated expression. Recently we have 
cloned several members of a family of cAMP- 
responsive enhancer-binding proteins (CREBs) 
and have discovered a domain on one of the 
CREBs that is phosphorylated by the cAMP- 
dependent protein kinase A, as well as by addi- 
tional protein kinases. The phosphorylation of 
CREB has the profound effect of increasing the 
transactivation of gene transcription. 
Discovery of an Insulinotropic Peptide 
We have discovered two new glucagon-like 
peptides related in structure to pancreatic gluca- 
gon and co-encoded for glucagon in the prohor- 
mone (proglucagon) . These peptides are differ- 
entially cleaved from the proglucagon, the initial 
translation product, in the pancreas and the intes- 
tines. One of the peptides, glucagon-like pep- 
tide-I (7-37), produced in the intestine and re- 
leased in response to oral nutrients has potent 
insulinotropic activities. Concentrations as low 
as 10""- 10"'^ M stimulate insulin secretion in 
the perfused rat pancreas and stimulate both 
cAMP formation and proinsulin mRNA levels in 
insulinoma cell lines. We have determined that 
the glucagon-like peptide regulates insulin se- 
cretion in humans and may be involved in the 
pathogenesis of certain types of diabetes mellitus 
due to faulty regulation. Particular emphasis is on 
analyses of the i8-cell receptor for the glucagon- 
like peptide and the mechanisms operative in the 
stimulation of insulin gene transcription in re- 
sponse to the actions of the peptide. 
Our goals are 1) to characterize further the 
genes encoding the regulatory (DNA-binding) 
proteins that interact with tissue-specific en- 
hancers and to determine how cAMP-mediated 
expression of the peptide hormone-encoding 
genes is regulated in the specific cellular pheno- 
types and 2) to test further the new glucagon-like 
peptides for their potential regulatory actions 
within the pancreatic islets and the intestinal 
tract and to explore the possible role of the pep- 
tides in diabetes mellitus. 
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