with atherosclerosis, although the mechanism by 
which it accelerates this process is obscure. In col- 
laboration with the laboratory of Dr. Richard Lawn 
(Genentech), Dr. Hammer's laboratory is introduc- 
ing fusion genes consisting of the mouse MT or 
transferrin promoter/enhancers and a human Lp(a) 
cDNA into the genome of mice. The intent is to ex- 
press this foreign product in this species and use 
these mice to begin to investigate the role of Lp(a) 
in the progression of atherosclerosis. 
II. Cell-specific Gene Expression. 
A. Rat elastase and trypsin genes. The serine prote- 
ases are a family of digestive enzymes whose genes 
are expressed selectively in acinar cells of the exo- 
crine pancreas. In collaboration with Dr. Ray Mac- 
Donald (University of Texas Southwestern Medical 
Center at Dallas), Dr. Hammer is continuing to 
characterize the regulatory domains within the 
elastase I gene and most recently the rat trypsin I 
gene that direct cell-specific expression. 
The elastase I gene contains a 134 bp enhancer 
that, when fused to a human growth hormone 
(hGH) gene, is sufficient to direct high levels of 
pancreas-specific expression in an orientation-, dis- 
tance-, and position-independent manner. This en- 
hancer consists of at least three domains, any two 
of which are sufficient to direct acinar cell-specific 
expression in mice. Experiments are now in prog- 
ress to determine the importance of each of these 
domains to cell-specific transcription. 
To elucidate the cis- and trans-acting factors that 
regulate acinar cell-specific gene expression, Dr. 
Hammer and his colleagues have conducted experi- 
ments to define the pancreas-specific enhancer of 
trypsin I, another serine protease gene. Transgenic 
mice were made that contained one of four 5'- 
trimmed rat trypsin-hGH genes and were analyzed 
for growth hormone gene expression. Trypsin gene 
expression is controlled by a 229 bp regulatory ele- 
ment located between -225 and +4 of rat trypsin 
5 '-flanking DNA that confers cell-specific transcrip- 
tion. A smaller 130 bp fragment of rat trypsin I from 
-126 to +4 was unable to direct expression of the 
hGH gene. The 229 bp DNA fragment contains the 
putative pancreas-specific enhancer, which is 
shared among the pancreatic genes. Surprisingly, 
hGH expression was detected in the stomach of 
some transgenic mice bearing the rat trypsin-hGH 
gene. The pancreatic genes trypsin, amylase, and 
elastase were expressed in the glandular stomach, a 
cell type not previously known to produce these 
products. Experiments are in progress to define fur- 
ther the 5' elements of other members of the serine 
protease gene family that direct acinar cell-specific 
gene transcription. 
B. Rat phosphoenolpyruvate carboxykinase 
(PEPCK) gene. The cytosolic enzyme PEPCK is a 
pace-setting enzyme in gluconeogenesis, which is 
expressed primarily in the liver, kidney cortex, and 
adipose tissue. The synthesis of this enzyme is con- 
trolled in a differential manner in these three tis- 
sues. In liver, the levels of PEPCK are induced by 
cAMP and glucocorticoids and are decreased by in- 
sulin. In contrast, kidney PEPCK is induced by 
changes in acid-base balance and by glucocor- 
ticoids. Although many of the elements that are in- 
volved in hormonal and dietary modulation of 
PEPCK expression have been defined, little informa- 
tion has been available on the regulatory elements 
that direct the cell-specific and temporal modula- 
tion of PEPCK gene expression. In collaboration 
with Drs. Elmus Beale (Texas Tech University) and 
Mark Magnusson (Vanderbilt University), Dr. Ham- 
mer is identifying and characterizing some of the 
regulatory elements that direct the cell-specific 
transcription of the PEPCK gene. 
Transgenic mice were made that contained one 
of five constructs consisting of various 5' deletions 
of the rat PEPCK gene fused to an hGH gene. Trans- 
genic animals containing these constructs are being 
screened for tissue-specific and developmental reg- 
ulation of gene expression, as well as hormonal 
and dietary modulation of hGH expression. 
III. Neoplasia. 
A. Cervical cancer. Squamous cell carcinoma of the 
uterine cervix is one of the most common cancers 
among women. Correlation between human papil- 
loma virus (HPV) infection of the uterine cervix and 
the development of cervical neoplasia is well estab- 
lished. HPV types 16 and 18 are found in more 
than 90% of all cervical tumors, suggesting that 
these viruses play a causative role in the develop- 
ment of this malignancy. Dr. Laimonis A. Laimins 
(HHMI, The University of Chicago) has demon- 
strated that the E6 and E7 gene products of HPV-16 
and HPV- 18 have transforming ability in NIH 3T3 
cells and Rat-1 cells. Transgenic mice containing an 
HPV-18 construct have been made, in collaboration 
with Dr. Laimins, to determine the causal relation- 
ships between E6 and E7 expression and cervical 
carcinoma. Of 16 founder mice containing the HPV- 
Continued 
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