GAL-4 DNA-binding domain, activate transcription 
of a UAS reporter only when the P box is present. 
The P-box sequence of 50 residues alone is suffi- 
cient to transactivate transcription. Analyses of both 
mRNAs and genomic DNA fragments indicate a con- 
siderable complexity of CREB and CREB-like prod- 
ucts. Curiously, several of the mRNAs and gene frag- 
ments hybridize to both CREB and jun cDNAs, 
although these two cDNAs do not cross-hybridize 
with each other. 
During the next year, research will be focused on 
more-detailed investigations of the functional do- 
mains of the cAMP-responsive DNA-binding protein. 
Studies will be aimed at defining the DNA-binding 
properties and the molecular processes of tran- 
scriptional activation. Emphasis will be on investi- 
gations of the roles of phosphorylation and 
glycosylation in nuclear transport, DNA binding, di- 
merization, and coupling to other transcription fac- 
tors. The structure of the CREB gene and the diver- 
sity of additional CREB-like gene products in other 
tissues will be investigated. Efforts will be made to 
isolate the cDNAs encoding the upstream and 
downstream DNA-binding proteins that coopera- 
tively enhance cAMP-mediated activation of tran- 
scription of the gonadotropin a and somatostatin 
genes. 
Dr. Habener has also examined the cell-specific 
post-translational processing of proglucagon. Pre- 
viously he determined the sequence of the rat 
glucagon gene and discovered that the gene en- 
PUBLICATIONS 
codes a prohormone that includes not only 
glucagon but also two additional peptides related 
in structure to glucagon, termed glucagon-like pep- 
tides. Marked differences in the pattern of post- 
translational processing of glucagon were found in 
rat pancreas, which produces glucagon, and intes- 
tine, which produces predominantly glucagon-like 
peptides. 
Having established that proglucagon encodes 
new glucagon-like peptides. Dr. Habener investi- 
gated the potential biologic activities of these new 
peptides. He discovered that glucagon-like peptide- 
I (GLP-I) is a potent insulinotropic peptide. When 
studied in pancreatic islet cell lines, GLP-I (7-37) 
stimulates insulin gene transcription, cAMP forma- 
tion, and insulin secretion at concentrations in the 
picomolar range. Moreover, GLP-I (7-37) stimulates 
insulin release in the perfused rat pancreas at con- 
centrations as low as 10"^^ M. Dr. Habener has de- 
termined that the pancreatic P-cell receptor for 
GLP-I is distinct from that of glucagon in hepatic 
cells. Administration of the synthetic peptide to 
human volunteers results in a marked increase of 
plasma insulin levels followed by a fall in blood glu- 
cose levels. Dr. Habener is planning to test the pos- 
sible therapeutic properties of GPL-I in patients 
with non-insulin-dependent diabetes mellitus. 
Dr. Habener is also Professor of Medicine at Har- 
vard Medical School and Associate Physician at Mas- 
sachusetts General Hospital. 
Books and Chapters of Books 
Habener, J. E, Deutsch, PJ., Hoeffler, J.P, and Jameson, J. L. 1988. Eunctional dissection of a cAMP-response el- 
ement using recombinant mutations. In Molecular Biology of Brain and Endocrine Peptidergic Systems 
(Chretin, M., and McKerns, K.W, Eds.). New York: Plenum, pp 1-12. 
Habener, J.F., and Potts, J.T., Jr. 1988. Clinical features of primary hyperparathyroidism. In Endocrinology 
(DeGroot, LJ., Cahill, G.F., Jr. , Martini, L., Nelson, D.H., Odell, WD., Potts, J.T., Jr., Steinberger, E., and 
Winegrad, A.I., Eds.). New York: Grune & Stratton, 2nd ed, vol 2, pp 954-966. 
Articles 
Brasier, A.R., Tate, J., Ron, D., and Habener, J.E. 1989. Multiple cis-acting DNA regulatory elements mediate 
hepatic angiotensinogen gene expression. Mol Endocrinol 3:1022-1034. 
Campbell, DJ., and Habener, J.E. 1989. Hybridization in situ studies of angiotensinogen gene expression in 
rat adrenal and lung. Endocrinology 124:218-222. 
Deutsch, RJ. , Hoeffler, J.E , Jameson, J.L., and Habener, J.E. 1988. Cyclic AMP and phorbol ester-stimulated 
transcription mediated by similar DNA elements that bind distinct proteins. Proc Natl Acad Sci USA 
85:7922-7926. 
Continued 
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