Regulation of Keratin Gene Expression 
As agents for targeting expression of foreign genes 
in skin and for altering expression patterns of genes 
involved in growth and differentiation, the pro- 
moters of epidermal keratin genes -will be invalu- 
able. This laboratory isolated and characterized the 
functional genes encoding K5 and Kl4. They 
showed that K5/K14 transcriptional rates in keratin- 
ocytes are high, and they have partially character- 
ized sequences directing proper tissue-specific 
expression. 
Two Kl4 regulatory elements were identified that 
act synergistically with a TATA box to drive expres- 
sion in keratinocytes in vitro and in transgenic 
mice. Analyses of the proximal domain revealed an 
essential 10-bp palindrome that specifically binds 
the nuclear factor AP-2. AP-2 is prevalent in epider- 
mal and neural cells, and AP-2 sites occur in pro- 
moter regions of many epidermal genes. The distal 
element of the Kl4 gene is more complex, contain- 
ing both positive and negative elements, and studies 
are under way to analyze these elements. Parallel 
studies are in progress to delineate sequences re- 
sponsible for human K5 gene expression, and it is 
already clear that many of the same regulatory ele- 
ments are shared by these coexpressed genes. Addi- 
tionally, studies have been initiated to dissect out 
elements involved in keratin gene switching during 
differentiation. Because 1) skin from founder trans- 
genic mice can readily be biopsied and analyzed, 2) 
skin contains ~20 different cell types, 3) pure epi- 
dermis can readily be separated from the rest of skin, 
and 4) K5 and Kl4 genes are the major structural 
proteins of basal keratinocytes, these genes are 
among only a few that are particularly amenable to 
an in vivo study of tissue-specific and differentia- 
tion-specific gene expression. 
Regulators of Epidermal Growth 
and Differentiation in Vitro 
and in Vivo 
Previously, this laboratory optimized conditions 
for cultivation of human epidermal cells, squamous 
cell carcinomas, and human papillomavirus-trans- 
fected keratinocytes such that most of their dififeren- 
tiative and altered epidermal phenotypes are main- 
tained. These researchers have utilized this system 
to examine the effects of TGF-a (transforming 
growth factor-a), TGF-jSs, retinoids, KGF (keratino- 
cyte growth factor), TNF-a (tumor necrosis factor- 
a), and interleukins on keratinocyte growth and dif- 
ferentiation. Of special interest is the keratinocyte 
autocrine growth factor TGF-a, whose levels are 
higher in skin from patients with psoriasis, squa- 
mous cell carcinomas, and other hyperproliferative 
skin diseases. The laboratory has used the Kl4 pro- 
moter to target overexpression of TGF-a to the basal 
layer in transgenic mouse skin. These studies re- 
vealed that 1) TGF-a is involved in calibrating epi- 
dermal thickness, a phenomenon that appears to be 
mediated by epidermal growth factor (EGF) recep- 
tor levels; 2) at high levels, TGF-a can bypass the 
need for a tumor initiator in generating wound- or 
tissue plasminogen activator (TPA) -induced papil- 
lomas; and 3) TGF-a generates some but not all of 
the features of psoriasis. 
In the past year this group has begun to follow up 
on these observations. Their findings include dem- 
onstrations that 1) TPA-induced papillomas in TGF- 
a mice do not have mutations in Ha-ra5, as do chemi- 
cally induced papillomas; and 2) two other factors, 
interleukin-6 (IL-6) and TNF-a, elevated in psoriatic 
epidermal cells, can elicit in transgenic mice cer- 
tain responses typical of psoriasis that are not in- 
duced by TGF-a. The demonstration that the Kl4 
promoter can be used to target expression of genes 
to stratified squamous epithelia has set the founda- 
tion for a powerful approach to examine the molecu- 
lar basis for a number of different human skin dis- 
eases and to provide important animal models for 
the treatment of these diseases. 
Dr. Fuchs is also Professor of Molecular Genet- 
ics and Cell Biology and of Biochemistry and Mo- 
lecular Biology at the University of Chicago. 
Books and Chapters of Books 
Fuchs, E. 1992. Of mice and men: genetic skin dis- 
eases arising from defects in keratin filaments. In 
Cell and Molecular Biology (Wolfe, S.L., Ed.). 
Belmont, CA: Wadsworth, pp 498-500. 
Articles 
Albers, K., and Fuchs, E. 1992. The molecular biol- 
ogy of intermediate filament proteins. Int Cytol 
Rev 134:243-279. 
Cheng, J., Turksen, K., Yu, Q.-C, Schreiber, H., 
Teng, M., and Fuchs, E. 1992. Cachexia and 
graft-versus-host-disease-type skin changes in ker- 
atin promoter-driven TNF-a transgenic mice. 
Genes Dev 6:1444-1456. 
Coulombe, P.A., Hutton, M.E., Letai, A., Hebert, A., 
Paller, A.S., and Fuchs, E. 1991 . Point mutations 
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