been investigated by the laboratory of Investigator 
E Reed Larsen, M.D. (Brigham and Women's Hospi- 
tal). The first is the process by which thyroxine, the 
prohormone secreted by the thyroid gland, is acti- 
vated. This apparently simple reaction, the loss of 
an iodine atom, is tightly controlled by at least two 
enzymes that function to ensure adequate supplies 
of the active hormone under various circumstances. 
In the past year considerable progress has been 
made in the analysis of the structure of these en- 
zymes. The second facet of Dr. Larsen's studies has 
been the identification of the thyroid-responsive se- 
quences in the promoter region of genes that allow 
them to respond to thyroid hormone. A repeated 
pattern of three nearly identical segments of six 
specific nucleotides is required for a gene to be re- 
sponsive to thyroid hormone. Surprisingly, at least 
some thyroid hormone-responsive genes cannot be 
expressed at maximum rates. This important obser- 
vation may increase understanding of the role of 
thyroid hormone in the regulation of many basic 
metabolic processes in health and disease. 
Investigator Joel F. Habener, M.D. (Massachusetts 
General Hospital) and his colleagues are studying 
the molecular mechanisms responsible for the reg- 
ulation and cell-specific expression of genes encod- 
ing polypeptide hormones. Their work has led to 
the hypothesis that the combinatorial interactions 
of several DNA sequence elements and DNA-bind- 
ing proteins result in the selective activation of spe- 
cific genes in phenotypically distinct cells. Their 
current work is focused on the cell-specific and 
cAMP-mediated activation of the somatostatin and 
gonadotropin subunit genes and the cell-specific 
expression of the glucagon and angiotensinogen 
genes that are expressed in the pancreas and liver. 
Ultimately they hope to isolate and characterize 
structurally the cAMP-responsive DNA-binding 
phosphoproteins and to analyze the molecular in- 
teractions of these proteins with the specific DNA 
sequence elements. 
Steroid hormones play essential roles in salt and 
water balance, in carbohydrate metabolism, and in 
reproduction. Their biosynthesis requires the ac- 
tion of a related group of enzymes that convert 
cholesterol to biologically active steroids. The labo- 
ratory of Assistant Investigator Keith L. Parker, M.D., 
Ph.D. (Duke University) is studying the factors that 
regulate the production of these steroidogenic en- 
zymes in the adrenal gland. So far they have been 
able to define some of the DNA regulatory elements 
and the proteins that interact with them to control 
the expression of these enzymes. Efforts to purify 
the proteins that are most important for the regu- 
lated expression of the sequences are under way. 
Investigator Robert J. Lefkowitz, M.D. (Duke Uni- 
versity) reports the following accomplishments 
over the past year: 1) the delineation of the struc- 
tural basis of ^-adrenergic receptor function by a 
combination of approaches, including site-directed 
mutagenesis and the creation of chimeric or hybrid 
receptors; 2) the demonstration that the function 
of the P-adrenergic receptor is regulated by phos- 
phorylation by the cAMP-dependent protein kinase 
and the P-adrenergic receptor kinase; 3) the suc- 
cessful cloning of the cDNA for the P-adrenergic re- 
ceptor kinase, which appears to be the first se- 
quenced member of a multigene family of receptor 
kinases that may have broad regulatory signifi- 
cance; and 4) the cloning of the genes for several 
new members of the adrenergic receptor family, in 
particular two new ttj-adrenergic receptor sub- 
types. These last studies suggest that the adrenergic 
receptor family is more heterogeneous than had 
previously been suspected and open the possibility 
of developing new, more-selective clinical therapeu- 
tic agents. 
Protein traffic across distinct cellular membranes 
occurs by a sort of biological zip code system. The 
recognition of the various signal sequences that 
constitute the zip codes requires the intervention 
of complex cellular machineries, referred to as 
translocons. Each translocon is composed of at 
least four entities: 1) a soluble signal recognition 
factor (SRF) that is specific for each translocon, 2) a 
membrane-bound homing receptor specific for 
each SRF, 3) a channel in the membrane that is 
opened upon presentation of a translocon-specific 
signal sequence and is closed after a single protein 
is translocated, and 4) a translocon-specific signal 
peptidase that removes the signal sequences. The 
laboratory of Investigator Giinter Blobel, M.D., 
Ph.D. (The Rockefeller University) has been investi- 
gating four different translocons. In addition he 
and his colleagues have continued their studies of 
the nuclear pore complexes and the lamina-associ- 
ated components that are key structures involved 
in the functional organization of the genome. 
Investigator John A. Glomset, M.D. (University of 
Washington) reports that research done in collabo- 
ration with Dr. Andreas Habenicht (University of 
Heidelberg) has identified a new role for plasma 
low-density lipoproteins: namely, delivery of the 
polyunsaturated fatty acid arachidonic acid to repli- 
cating cells. This role was shown to have a critical 
effect on the formation of two important regulatory 
Continued 
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