Mechanisms of Gene Regulation in Animal Cells 
Robert Tjian, Ph.D. — Investigator 
Dr. Tjian is also Professor of Biochemistry 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 in- 
vestigator there before moving to Berkeley. His honors include the Pfizer Award for Enzymology and the 
Monsanto Molecular Biology Award of the National Academy of Sciences. 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 bio- 
chemical process called transcription, which 
subsequently leads to the production of specific 
proteins in animal cells. We have devised various 
means of isolating the individual components of 
the cell responsible for transcription and have re- 
constructed this complex reaction in the test 
tube. In this way we can study how specific genes 
are turned on and off during cell growth and de- 
velopment. The mechanisms that govern the 
switching on and off of genes are of fundamental 
importance in understanding the normal meta- 
bolic processes that maintain and perpetuate liv- 
ing cells, as well as in deciphering the basis of 
disease and other cellular or genetic disorders. 
Biochemical Analysis of Cancer Genes 
A living cell contains hundreds of thousands of 
protein molecules, each carrying out its proper 
function. If either the production or the action of 
such proteins is altered, severe malfunction can 
result, such as uncontrolled growth leading to 
cancer. Among a normal cell's constituents, cer- 
tain key molecules have the potential to be onco- 
genic, or tumor causing. Such molecules are 
called oncoproteins. Our group previously iso- 
lated a family of rare proteins from human cells 
that have been shown to be oncoproteins, en- 
coded by the genes jun and fos. These regulatory 
proteins are normally involved in controlling the 
action of many other genes in the cell, 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 reveal that the ability of the jun pro- 
tein to activate transcription is regulated by a 
cell-type-specific inhibitor that interacts with a 
unique portion of the molecule, rendering it less 
potent. The isolation and characterization of this 
specific negative regulator should help unravel 
the molecular signaling pathways responsible for 
transducing information from the outside of the 
cell into the nucleus, where gene expression is 
controlled. Such inhibitors of jun activity may 
represent new members of the anti-oncogenic or 
tumor suppressor family of biological regulatory 
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 these rare and fragile proteins. Through 
the use of specific DNA-afi&nity chromatography 
procedures pioneered in our laboratory, we can 
now isolate transcription proteins that in turn en- 
able us to clone the genes that encode these im- 
portant regulatory proteins. The ability to isolate 
this biologically important class of genes pro- 
vides a powerful approach for studying their 
structure and function. 
In the past several years our laboratory has iso- 
lated and characterized some 10 difi'erent genes 
that are directly responsible for the tissue-selec- 
tive, temporally programmed, and basal-level 
control of gene expression in animal cells. These 
studies are beginning to reveal new concepts re- 
garding the surprisingly modular construction of 
these proteins, as well as their unusual plasticity 
and functional flexibility. Most importantly, spe- 
cific structural motifs that lie within these 
proteins have been recognized as carrying out 
distinct functions. Our findings provide the theo- 
retical basis for analysis of other as yet undiscov- 
ered transcription factors and will greatly aid our 
ability to decipher their mechanisms of action. 
How Promoter-Specific Regulators Trigger 
Transcription 
One fundamental mystery is the mode of action 
by which sequence-specific DNA-binding pro- 
teins such as the prototype human factor Spl di- 
rect transcriptional interactions. To address this 
critical issue, we recently fractionated and iso- 
lated the multiple components necessary to re- 
constitute transcription. In the process of dissect- 
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