Mechanisms of Gene Regulation in Animal Cells 
Robert Tjian, Ph.D. — Investigator 
Dr. Tjian is also Professor of Molecular and Cell Biology at the University of California, Berkeley, and 
Adjunct Professor of Biochemistry and Biophysics at the University of California, San Francisco. He 
received the Ph.D. degree in biochemistry and molecular biology from Harvard University. Following this 
he was a Junior Fellow of the Harvard Society of Fellows while a resident at Cold Spring Harbor Laboratory 
and later a staff investigator there before moving to Berkeley. His honors include the Monsanto Molecular 
Biology Award of the National Academy of Sciences and the Pfizer Award for Enzymology. Dr. Tjian was 
recently elected to the National Academy of Sciences. 
THE main research interest of our laboratory is 
the mechanism by which the genetic infor- 
mation stored in DNA molecules is retrieved in a 
controlled and orderly fashion during the process 
called transcription, which leads to the produc- 
tion of specific proteins in animal cells. We have 
taken a biochemical approach to the problem of 
gene control and have devised various means of 
isolating the cellular components responsible for 
transcription and of reconstructing this complex 
reaction in the test tube. In this way we are study- 
ing how specific genes are turned on and off dur- 
ing cell growth and development of eukaryotic 
organisms. The mechanisms that govern the acti- 
vation of genes are of fundamental importance in 
understanding the normal metabolic processes 
that maintain and perpetuate living cells, as well 
as in deciphering cellular and genetic disorders. 
Biochemical Analysis of Cancer Genes 
A living cell contains hundreds of thousands of 
protein molecules, each carrying out its allotted 
function. However, if either the production or 
action of these molecules is altered, severe mal- 
function can result, such as uncontrolled growth 
leading to cancer. Thus certain key molecules in 
the milieu of a normal cell's constituents have 
the potential to cause tumors when their func- 
tion is disrupted. Such molecules are called 
oncoproteins. 
Our group previously isolated from human 
cells a family of rare proteins that have subse- 
quently been shown to be oncogenic, encoded by 
thejun and fos genes. These regulatory proteins 
are normally involved in controlling the action of 
many other genes, but when their activities are 
perverted — for example, by viruses — they can 
lead to the production of cancer-causing cells. 
Recent advances in the study of the nuclear on- 
cogene ^wn reveal that the ability of its protein to 
activate transcription is regulated by a cell-rype- 
specific inhibitor that interacts with a unique 
portion of the molecule, rendering it less potent. 
It is anticipated that the isolation and character- 
ization of this specific negative regulator of jun 
will help unravel the molecular signaling path- 
ways responsible for transducing information 
from the outside of the cell into the nucleus, 
where gene expression is controlled. Moreover, 
such inhibitors of jun activity may also be found 
to represent new members of the anti-oncogenic 
or tumor-suppressor family of biological regula- 
tory molecules. 
Studies of Trans-activating Proteins 
That Regulate Gene Expression 
A major hurdle has been the development of 
biochemical techniques that allow the purifica- 
tion of certain rare and fragile regulatory pro- 
teins. Through use of DNA-affiniry chromatogra- 
phy procedures pioneered in this laboratory, it is 
now possible to isolate such transcription pro- 
teins and, in turn, to clone molecularly the genes 
that encode them. The ability to proliferate this 
biologically important class of genes provides a 
powerful approach toward understanding their 
structure and function. In the past two years the 
laboratory has isolated and characterized some 
10 different genes that are directly responsible 
for the tissue-selective, temporally programmed, 
and basal-level control of gene expression in ani- 
mal cells. 
In addition, these recent studies are beginning 
to reveal new concepts regarding the surprisingly 
modular construction of the derivative proteins 
as well as their unusual plasticity and functional 
flexibility. Most importantly, specific structural 
motifs that lie within these proteins have been 
recognized as carrying out distinct functions. 
These findings provide the theoretical basis for 
analysis of other as yet undiscovered regulatory 
factors and will greatly aid our ability to decipher 
their mechanisms of action. 
How Promoter-Specific Regulators 
Trigger Transcription 
One of the remaining fundamental mysteries is 
the mode of action by which sequence-specific 
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