small peptide-coding sequence immediately in 
front of the receptor-coding sequence on (32-recep- 
tor mRNA. 
Investigator Robert J. Lefkowitz, M.D. (Duke Uni- 
versity) and his colleagues report that their major 
accomplishments over the past year were 1) discov- 
ery of mutations of G protein-coupled receptors 
that constitutively activate the receptors and a de- 
lineation of their properties; and 2) discovery of the 
role of protein isoprenylation in the translocation 
and function of G protein-coupled receptor ki- 
nases, such as /3ARK (/3-adrenergic receptor kinase) 
and rhodopsin kinase. 
Work in the laboratory of Associate Investigator 
Roeland Nusse, Ph.D. (Stanford University) is fo- 
cused on a group of genes that exemplify the link 
between cancer and the control of normal devel- 
opment. The prototypic member of this group is 
Wnt-1, an oncogene in mouse breast cancer, but 
normally only expressed in the developing brain of 
a mouse embryo. This research group wishes to un- 
derstand the mechanism of action of the Wnt- 1 gene 
family during embryogenesis and to extrapolate 
these findings to cancerous growth. One model sys- 
tem under study is the fruit fly Drosophila, where 
the homologue of Wnt- 1 is identical to a develop- 
mental gene called wingless. Because of the exten- 
sive genetic analysis of Drosophila embryogenesis, 
the interactions of Wnt- 1 /-wingless with other genes 
can be conveniently studied. 
When adenovirus infects human cells, it repli- 
cates to produce progeny virus, and the cell is 
killed. When rodent cells are infected, the viral rep- 
lication cycle cannot be completed. Some of the in- 
fected cells are not killed and become oncogeni- 
cally transformed. In fact, some adenoviruses 
induce tumor formation when inoculated into ro- 
dents. The laboratory of Investigator Thomas E. 
Shenk, Ph.D. (Princeton University) seeks to define 
mechanisms underlying adenovirus gene regulation 
in infected human cells and tumor induction in ro- 
dents. Studies of the regulation of gene expression 
have focused on the adenovirus El A protein, the 
first viral protein expressed within infected ceils 
and the main adenovirus regulatory protein, activat- 
ing the synthesis of mRNAs from all remaining viral 
genes. Work is in progress to elucidate the mecha- 
nisms by which the E 1 A protein interacts with cellu- 
lar regulatory proteins to control mRNA synthesis. 
Studies of tumor induction have focused on an ade- 
novirus that can induce mammary tumors in rats. 
The ElA and ElB viral gene products are well 
known to play a role in adenovirus oncogenesis. 
However, the formation of mammary tumors re- 
quires an additional protein encoded by the adeno- 
virus E4 gene. Work is in progress to probe the func- 
tion of this newly identified oncoprotein. 
Assistant Investigator Sandra L. Wolin, M.D., Ph.D. 
(Yale University) and her colleagues are interested 
in understanding post-transcriptional mechanisms 
for regulating gene expression in eukaryotic cells. 
One focus of her group has been the factors that 
affect ribosome movement along mRNAs during 
translation. Using a method that allows the detec- 
tion and mapping of paused ribosomes on the 
mRNA, they have identified a new intermediate in 
translation initiation in which a fully assembled ri- 
bosome pauses over the initiation codon. They are 
determining what features of mRNA sequence and 
structure result in ribosome pausing and in frame- 
shifting during the translation of retroviral mRNAs. 
In a separate project, the laboratory is investigating 
the structure and function of a conserved class of 
small cytoplasmic ribonucleoprotein particles, the 
Ro RNPs, often the targets of autoantibodies in pa- 
tients with certain rheumatological disorders. 
Messenger RNt^s (mRNAs) , the functional transla- 
table intermediates of gene expression, are formed 
in the nuclei of eukaryotic cells by extensive and 
tightly regulated post-transcriptional processing of 
heterogeneous nuclear RNAs (hnRNAs) , the primary 
RNA polymerase II transcripts. Throughout the time 
they are in the nucleus, hnRNAs are associated with 
proteins — the hnRNPs. These proteins influence 
the structure of hnRNAs and therefore their fate and 
processing into mRNAs. The hnRNPs are as abundant 
in growing vertebrate cells as histones, and hnRNA- 
hnRNP complexes are thus also of interest, because 
they are major nuclear structures. In the cytoplasm, 
mRNAs are associated with mRNPs, and these are 
likely to be involved in the regulation of the transla- 
tion and stability of mRNAs and in their cellular lo- 
calization. The goal of Investigator Gideon Drey- 
fuss, Ph.D. (University of Pennsylvania) and his 
colleagues is to understand, in molecular detail and 
cellular architecture, how the post-transcriptional 
portion of the pathway of gene expression operates 
in the cell. To do so they investigate the structure, 
function, and localization of the hnRNP and mRNPs, 
and hnRNP complexes. 
Investigations of experimental models of human 
disease in the laboratory of Investigator Mary -Jane H. 
Gething, Ph.D. (University of Texas Southwestern 
Medical Center at Dallas) grow out of several years 
of basic research on the biochemical and structural 
properties of cellular and viral proteins. Experi- 
ments involve three systems: 1 ) human tissue-type 
plasminogen activator, a serine protease involved in 
CELL BIOLOGY AND REGULATION 
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