Genetic Regulatory Mechanisms in Cellular Differentiation 
that NFAT might be the direct target of these 
drugs. 
We have found that NFAT is a complex hetero- 
dimeric protein: one subunit is constitutive, T 
cell-specific, and located in the cytoplasm of 
resting cells; the other subunit is located in the 
nucleus and is induced. The transcriptionally ac- 
tive protein forms when the cytoplasmic compo- 
nent translocates to the nucleus in response to 
stimulation through the antigen receptor of T 
cells. Cyclosporin A and FK-506 appear to func- 
tion by inhibiting the translocation, but they do 
not interfere with the induction of the nuclear 
component. Thus the prolyl isomerase may func- 
tion both as an isomerase and as a translocation 
molecule. 
Endodermal and Hepatocyte Differentiation 
Several years ago we identified a tissue-specific 
transcription factor, HNF-1, that interacts with 
essential regions of the promoters of a large fam- 
ily of genes expressed in endodermally derived 
tissues. During the past year we were able to pu- 
rify the protein, obtain the amino acid sequence 
from protease-derived fragments, and clone its 
gene. Not surprisingly, the protein contains a ho- 
meodomain similar to that found in genes deter- 
mining body form in insects. Curiously, the pro- 
tein dimerizes through a region in the amino 
terminus of the protein, unlike that found in 
other homeodomain-containing proteins. This 
led us to look for a protein that might heterodi- 
merize with it and hence diversify its regulatory 
capabilities. We found such a protein by screen- 
ing a hepatocyte cDNA library at low stringency. 
This protein, HNF-l/?, which is expressed in an 
overlapping group of tissues with HNF-1 a, con- 
tains a dimerization and homeodomain similar to 
those of HNF-1 a but a different transcriptional 
activation domain. The HNF-1 ;S pattern of ex- 
pression indicates that it is a repressor rather than 
activator of genes selectively expressed in the 
liver. During the coming year, we will investigate 
the role of these proteins in mammalian endoder- 
mal development. 
98 
