is mediated through a common transcription factor 
or metabolic switch protein. Assistant Investigator 
Maria C. Alexander-Bridges, M.D., Ph.D. (Massachu- 
setts General Hospital) and her colleagues have 
cloned a trans-acting factor, IRE-ABP (insulin re- 
sponse element-A-binding protein), that is regu- 
lated by insulin and nutritional manipulations that 
result in hyperinsulinemia. This factor interacts 
with many genes that are regulated during the adap- 
tive response of the organism to hyperinsulinemia. 
IRE-ABP may be a multifunctional transcriptional 
regulator that promotes a metabolic switch in re- 
sponse to glucose and insulin. 
Investigator Perry J. Blackshear, M.D., D.Phil. 
(Duke University) and his colleagues are studying 
the molecular mechanisms of action of insulin and 
related polypeptide growth factors. They hope even- 
tually to explain the biochemical steps between 
binding of these hormones to their cell surface re- 
ceptors and such subsequent events in the cell as the 
activation of enzymes or the rapid turning on of spe- 
cific genes. Characterization of these pathways 
should increase an understanding of the normal 
physiological responses to these hormones, as well 
as of the molecular defects that occur in the insulin 
resistance characteristic of obesity and common 
types of diabetes mellitus. 
Thyroid hormones are essential for the regulation 
of general metabolism, growth, and development. 
Investigator William W. Chin, M.D. (Brigham and 
Women's Hospital) has been studying the molecular 
mechanisms by which thyroid hormones regulate 
gene expression. He has focused on the transcrip- 
tional factors (thyroid hormone receptors and nu- 
clear auxiliary factors) in this process and has pro- 
vided important clues regarding the role of ligand 
(thyroid hormone) and protein-protein interac- 
tions. It is hoped that such information will provide 
insight into hormone regulation of gene expression, 
in general, and specifically the mechanism of thy- 
roid hormone action. For example, it may permit an 
understanding of the mechanisms involved in defec- 
tive signaling in the syndrome of generalized thy- 
roid hormone resistance. 
Steroid hormones play essential roles in salt and 
water balance, sugar metabolism, and reproduction. 
Their biosynthesis requires the action of a related 
group of enzymes, and Assistant Investigator Keith L. 
Parker, M.D., Ph.D. (Duke University) and his col- 
leagues are studying the factors that regulate the pro- 
duction of these enzymes in the adrenal gland. They 
have defined regulatory elements and proteins that 
control the expression of these enzymes. One pro- 
tein interacts with promoter elements from all of the 
steroid hydroxylases, implying a pivotal role in their 
coordinate expression. This protein is one of the 
nuclear receptor proteins, a diverse group of struc- 
turally related proteins that are involved in the re- 
sponses to such diverse agents as steroids, thyroid 
hormone, and vitamin D. The same gene that regu- 
lates the steroid hydroxylases also plays an impor- 
tant role in early embryonic development through 
the production of another protein that has both 
shared and distinct structural features. Ongoing 
studies of this key transcriptional regulator should 
provide important insights into the mechanisms that 
control steroid hormone biosynthesis and may pro- 
vide novel concepts about the differentiation of 
steroidogenic tissues. 
Many hormones and grovi^h factors act by stimu- 
lating the breakdown of specific membrane lipids. 
This leads to the generation of the signaling mole- 
cules controlling the activities of protein kinases 
that phosphorylate important cellular proteins. Re- 
search in the laboratory of Investigator John H. Ex- 
ton, M.D., Ph.D. (Vanderbilt University) has identi- 
fied proteins and unexpected mechanisms that are 
involved in regulating the breakdown of the lipids. 
The new proteins are some that transduce signals 
from cell surface receptors for hormones (G pro- 
teins) or that catalyze the breakdown of the lipids 
(phospholipases). The new mechanisms are those 
involving unexpected components of the G proteins 
and actions of protein kinases that do not involve 
phosphorylation. 
Guanylyl cyclase receptors exist within the cyto- 
plasm as well as the membranes of most cells. Inves- 
tigator David L. Garbers, Ph.D. (University of Texas 
Southwestern Medical Center at Dallas) and his col- 
leagues have found that one receptor, responsible 
for acute secretory diarrhea when stimulated by bac- 
terial peptides, responds normally to an endoge- 
nous peptide named guanylin. The receptor and 
guanylin also appear to exist in tissues outside the 
intestine. A cDNA clone for guanylin has now been 
obtained and is being used to define its function in 
the intestine as well as in other tissues. 
Adrenergic receptors play an important role in the 
control of cardiovascular function by the central 
nervous system. During the past year members of the 
research group of Assistant Investigator Brian K. Ko- 
bilka, M.D. (Stanford University) have learned more 
about the structure of these receptors, how they are 
synthesized and inserted into a lipid bilayer, and the 
intracellular targeting and agonist-mediated redis- 
tribution of different subtypes of adrenergic recep- 
tors. Progress has also been made in understanding 
how 182-receptor synthesis may be regulated by a 
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