membrane IgM-associated proteins MB- 1 and 
are sufficient to promote surface expression of a 
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POLYPEPTIDE HORMONE GENE REGULATION 
Joel F. Habener, M.D., Investigator 
Major emphasis in Dr. Habener's laboratory is 
presently in two areas: 1) the characterization of 
DNA-binding proteins responsible for regulated and 
tissue-specific expression of polypeptide hormone 
genes and 2) determination of the bioactivities of 
peptides identified through nucleotide sequencing 
of precursors encoding peptide hormones. 
Nuclear proteins bind to specific DNA sequences 
in or around the polypeptide hormone genes, to up- 
or down-regulate the transcription of genes. A major 
goal is to isolate and characterize the structures and 
functions of the DNA-binding proteins, with particu- 
lar regard to the regulation of transcriptional transac- 
tivation functions by cellular signal transduction 
pathways involving protein phosphorylation. Dr. 
Habener is using pancreatic islet cell lines with dis- 
tinct hormone-expressing phenotypes to investigate 
cell-specific expression of the glucagon, somato- 
statin, insulin, and angiotensinogen genes. Similar 
studies of expression of the gonadotropin subunit 
and angiotensinogen genes are being analyzed in 
placental and liver cell lines, respectively. 
Dr. Habener has focused on the cis-control ele- 
ments and the transacting DNA-binding proteins re- 
sponsible for the cell-type-specific expression of 
the glucagon, somatostatin, and insulin genes, be- 
cause the expression of these polypeptide hormone 
genes is developmentally regulated during the dif- 
ferentiation of a stem neuroendodermal islet cell 
into specific hormone-producing phenotypes. Pro- 
moter regions involved in the regulation of the tran- 
scription of the three genes interact with a family of 
similar proteins related to the homeodomain helix- 
turn-helix proteins involved in tissue differentia- 
tion. By interacting with these DNA control ele- 
ments, these proteins collectively suppress or 
stimulate transcription of the genes. In addition. Dr. 
Habener has identified cAMP response elements 
(CREs) in the promoters of these three islet hor- 
mone genes. The CREs mediate cAMP-induced gene 
transcription and bind the bZIP proteins, so-called 
because their DNA-binding domains consist of a ba- 
sic region involved in DNA site-specific recognition 
and a coiled-coil leucine "zipper" responsible for 
dimerization. The bZIP proteins include fos, jun, 
C/EBP, and particularly a subgroup of proteins, the 
CREB/ATFs, which are CRE-binding proteins related 
to the activating transcription factors whose transac- 
tivation properties are stimulated by viral gene- 
encoded products. 
In his studies (supported in part by the National 
Institutes of Health) of the promoter that controls 
expression of the somatostatin gene in pancreatic 
islet cells. Dr. Habener has discovered SMS-UE, a 
DNA enhancer element. SMS-UE, a D cell-specific 
transcriptional regulator that acts synergistically 
with the CRE of the promoter, is a bipartite element 
with two interdependent functional domains, A and 
B. Domain A binds a CCAAT box-binding protein 
a-CBE, a transcription factor that also regulates 
expression of the human chorionic gonadotropin 
a-subunit gene. Domain B binds an islet cell- 
specific protein with characteristics similar to those 
of Isl- 1 , a transcriptional activator protein that binds 
to the E2 enhancer of the rat insulin- 1 gene. SMS-UE 
also binds transcription factor CREB, but not CREM, 
the close homologue of CREB, on a site adjacent to 
or overlapping the 3' end of domain B. Dr. Habener 
showed that the carboxyl-terminal bZIP domain of 
CREB binds to the CRE of the somatostatin gene but 
is not sufficient for binding to SMS-UE. He also dis- 
covered evidence suggesting that CREB-SMS-UE 
binding requires stabilization by a region of the pro- 
tein located within the transactivation domain. 
Analyses of both mRNAs and genomic DNA frag- 
ments indicate a considerable complexity of CREB 
CELL BIOLOGY AND REGULATION 67 
