Polypeptide Hormone Gene Regulation 
Joel F. Habener, M.D. — Investigator 
Dr. Habener is also Professor of Medicine at Harvard Medical School and Associate Physician and Chief 
of the Laboratory of Molecular Endocrinology in the Department of Medicine at Massachusetts General 
Hospital, Boston. He obtained his B.S. degree in chemistry at the University of Redlands and his M.D. 
degree at the University of California, Los Angeles. After medical residency training at the Johns Hopkins 
Hospital, he spent two years in research at the National Cancer Institute. Dr. Habener completed his 
medical training in endocrinology and metabolism at Massachusetts General Hospital. 
OUR laboratory seeks an understanding of the 
molecular processes involved in the regula- 
tion of gene expression. The general hypothesis 
being tested is that peptide hormones are impor- 
tant regulatory molecules in conveying informa- 
tion among cells via ligand-receptor interactions 
and corresponding signal transduction, resulting 
in the expression of specific genes. These pro- 
cesses are important in determining cellular meta- 
bolic responses such as secretory activity, cellu- 
lar differentiation, and growth. 
Peptides in Cellular Metabolism 
Peptides activate metabolic responses in cells 
by way of interactions with specific receptors on 
distant (endocrine), adjacent (paracrine), or the 
same (autocrine) cells. These ligand-receptor in- 
teractions lead to the activation of signal trans- 
duction pathways involving postulated cascades 
of protein phosphorylation enzymatically cata- 
lyzed by protein kinases, eventuating in the as- 
sembly of active transcriptional complexes. 
Under intensive investigation are two such signal- 
ing pathways mediated by cAMP-dependent pro- 
tein kinase A and by phospholipid/diacylglyc- 
erol-stimulated protein kinase C. A major focus of 
the laboratory is to understand how specific 
phosphorylated DNA-binding proteins interact 
with cognate DNA sequences and thereby induce 
gene expression. 
Genes Encoding Polypeptide Hormones 
We have determined the structures, organiza- 
tion, and regulation of the expression of genes 
encoding several of the polypeptide hormones. 
Our work has centered on the genes encoding the 
glucagon and glucagon-related peptides, somato- 
statin, insulin, angiotensinogen, and the gonado- 
tropins. These studies have progressed through 
several stages: 1) cloning of the genes and eluci- 
dation of their structures, 2) determinations of 
the DNA enhancer and suppressor sequences re- 
sponsible for the regulation of the transcriptional 
expression of the genes, and 3) isolation and char- 
acterization of DNA-binding proteins involved in 
the regulation of expression. These studies have 
led to the identification of cell-specific enhancer 
sequences within the "promoter" regions of the 
genes — sequences that determine in which cel- 
lular phenorype the genes are expressed and how 
gene transcription responds to activator sub- 
stances such as cAMP and phorbol esters. They 
have also led to the identification of complex, 
cell-specific post-translational processing of pro- 
tein precursors (prohormones) encoding the 
peptide hormones. 
Recently we determined that specific nuclear 
proteins bind to these important DNA enhancer 
sequences and that the binding specificities, as 
well as the transactivation activities, of these pro- 
teins are regulated by their phosphorylation. 
Regulation of Glucagon and Somatostatin 
Gene Expression 
Our analyses of the regulation of the expres- 
sion of the glucagon gene in pancreatic islet cell 
lines reveal that islet cell-specific expression re- 
sides in at least two enhancer-like sequences and 
that A cell expression in the islets is determined 
by an additional enhancer/promoter combina- 
tion. The expression of the somatostatin gene 
is restricted to the D cells because suppressor 
elements prevent expression in the glucagon- 
producing A cells and insulin-producing B cells. 
Transcriptional activation of the glucagon gene is 
mediated through both protein kinase C and pro- 
tein kinase A pathways, whereas activation of the 
somatostatin gene is regulated by protein kinase A 
and a calcium-regulated pathway. 
Cloning and Structure of a cAMP-Dependent 
DNA-binding Protein 
In studies of the somatostatin and gonadotro- 
pin genes, we have determined that their expres- 
sion is stimulated via a cAMP-dependent signal 
transduction pathway. We have discovered that 
DNA-binding proteins interact with specific, short 
DNA sequences to generate cAMP-responsive 
complexes. These DNA-protein complexes that 
mediate either cAMP or phorbol ester control of 
gene transcription share certain related struc- 
tures. Cooperative interactions among several 
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