I. PROGRAM IN CELL BIOLOGY AND REGULATION 
The Program in Cell Biology and Regulation is a 
continuation of the Institute's oldest research pro- 
gram, formed in 1976 under the title "Metabolic 
Regulation." In 1985 the program was renamed to 
reflect the Institute's growing activity in the area of 
molecular cell biology Investigators working in this 
area are located at the University of Michigan, The 
Carnegie Institution of Washington at Baltimore, 
the Brigham and Women's Hospital in Boston, the 
Massachusetts General Hospital, the Massachusetts 
Institute of Technology, The University of Chicago, 
the University of Texas Southwestern Medical Cen- 
ter at Dallas, Duke University, the University of 
Iowa, the University of California at both Los Ange- 
les and San Francisco, Vanderbilt University The 
Rockefeller University, the Oklahoma Medical Re- 
search Foundation, Stanford University, the Univer- 
sity of Pennsylvania, Princeton University, Washing- 
ton University in St. Louis, and the University of 
Washington. The studies being conducted under 
this program largely concern the metabolic path- 
ways and molecular processes that are basic to the 
growth and differentiation of cells, communication 
within and between cells, cell-substrate relation- 
ships, and some of the disorders that occur when 
these processes are perturbed. 
Senior Investigator Donald F. Steiner, M.D. (The 
University of Chicago) and his colleagues are con- 
tinuing their studies of the genetic and molecular 
mechanisms underlying the production and action 
of insulin and related regulatory hormones pro- 
duced in the islets of Langerhans of the pancreas. 
The biological roles of various precursor peptides, 
such as proinsulin, and the cell biological and enzy- 
matic mechanisms that lead to their transformation 
into active hormones or neuropeptides are also 
being studied. Their long-term goals are to develop 
information that will increase understanding of the 
production of insulin and its mode of action and of 
the growth and development of islet tissue, with a 
view to providing insights into the causes of human 
diabetes mellitus. 
Investigator Joseph Avruch, M.D. (Massachusetts 
General Hospital) continues to examine the se- 
quence of reactions by which insulin modifies cell 
function. The most significant findings in the past 
year relate to the purification of two proteins that 
are among the initial targets of the activated insulin 
receptor. 
The research of Investigator Perry J. Blackshear, 
M.D., D.Phil. (Duke University) is also focused on 
the biochemical reactions that occur when insulin 
binds to its receptor in the membrane cells and on 
some of the later molecular changes that this event 
initiates. One of the earliest such changes is the 
rapid turning on of the c-fos proto-oncogene. This 
response to insulin appears to involve a discrete 
segment of the c-fos gene. Dr. Blackshear's labora- 
tory is also trying to determine how insulin modi- 
fies the ability of certain proteins to bind to DNA 
and, in this way, to redirect the metabolic reactions 
of the responding cells. A more complete under- 
standing of the pathways involved should help to 
elucidate the process of normal cell growth, and 
such abnormalities as obesity and adult-onset dia- 
betes. 
In the absence of insulin there is a marked de- 
crease in the tissue content of a number of rate- 
limiting en2ymes that regulate the uptake and utili- 
zation of glucose. The laboratory of Assistant Inves- 
tigator Maria C. Alexander-Bridges, M.D., Ph.D. 
(Massachusetts General Hospital) has defined two 
cis-acting sequences in the glyceraldehyde-3-phos- 
phate dehydrogenase (GAPDH) gene that together 
increase the inductive effect of insulin on the tran- 
scription of the GAPDH gene. Insulin-sensitive 
DNA-binding proteins interact with these se- 
quences in fat and liver cells that store glucose as 
glycogen. Through her continuing studies Dr. Alex- 
ander-Bridges hopes to define the mechanisms by 
which insulin potentiates energy storage and to de- 
termine how the regulation of the GAPDH gene is 
altered in the diabetic state. 
The laboratory of Investigator William W Chin, 
M.D. (Brigham and Women's Hospital) is exploring 
the molecular mechanisms involved in the hor- 
monal regulation of gene expression. In the past 
year, their efforts have been focused largely on the 
thyroid hormone and the sex steroids that respec- 
tively regulate the genes for thyrotropin and gonad- 
otropin. Putative cis-acting DNA elements have 
been identified that appear to be critical for the re- 
sponse of these genes. In addition, an analysis of 
the molecular genetics of the various thyroid hor- 
mone receptor forms has demonstrated consider- 
able heterogeneity in their structure and function. 
The goal is to define more precisely the structure of 
the hormone receptors and their interactions with 
the DNA regulatory regions responsible for both 
the negative and positive regulation of the respon- 
sive genes. 
Two critical steps in thyroid hormone action have 
Continued 
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