Previously Dr. Cunningham's laboratory showed 
that the virus receptor is not expressed in liver. In 
the past year, they have identified a second trans- 
porter of cationic amino acids that is related to the 
virus receptor and is expressed in hepatocytes. This 
transporter has a much lower affinity — but greater 
transport capacity — for cationic amino acids than 
the MuLV receptor. These properties permit hepato- 
cytes to remove high levels of these amino acids 
from the portal vein after a large protein meal, but 
protect the plasma pool of arginine from the intra- 
cellular arginase required for urea synthesis within 
hepatocytes. 
A third cationic amino acid transporter arises by 
alternative splicing of mRNA derived from the gene 
encoding the liver transporter. Expression of this 
transporter is induced in macrophages activated by 
interferon-7 or tumor necrosis factor. These cyto- 
kines also decrease the expression of the virus re- 
ceptor. The inducible transporter may be required 
to supply macrophages with arginine, the substrate 
for synthesis of nitric oxide (NO), an important sig- 
naling molecule that moves freely from macro- 
phages to adjacent cells and can activate guanylate 
cyclase, resulting in the production of cGMP. In ad- 
dition, NO is a highly reactive free radical that is 
toxic to tumor cells and to intracellular pathogens, 
including those that cause tuberculosis, schistoso- 
miasis, leishmaniasis, toxoplasmosis, and malaria. 
In the past year, Dr. Cunningham and his co-workers 
have cloned a cDNA from activated macrophages 
that encodes nitric oxide synthase (NOS), the en- 
zyme that catalyzes the synthesis of NO from argi- 
nine. Using this clone, they have demonstrated coor- 
dinate expression of NOS and the transporter by 
cytokines. They are currently investigating the con- 
sequences of MuLV infection on NO production in 
macrophages. 
Dr. Cunningham is also Assistant Professor of 
Medicine at Harvard Medical School and Asso- 
ciate Physician at Brigbam and Women 's Hospi- 
tal, Boston. 
Articles 
Albritton, L.A., Bowcock, A.M., Eddy, R.L., Morton, 
C.C., Tseng, L., Farrer, L.A., Cavalli-Sforza, L.L., 
Shows, T.B., and Cunningham, J.M. 1992. The 
human cationic amino acid transporter (ATRCl): 
physical and genetic mapping to 13ql2-ql4. Ge- 
nomics 12:430-434. 
Bader, A., Rinkes, I.H.B., Closs, E.I., Ryan, CM., 
Toner, M., Cunningham, J.M., Tompkins, R.G., 
andYarmush, M.L. 1992. A stable long-term hepa- 
tocyte culture system for studies of physiologic 
processes: cytokine stimulation of the acute phase 
response in rat and human hepatocytes. Biotech- 
nol Prog 18:219-225. 
Cunningham, J.M. 1992. Cellular entry by murine 
retroviruses. Semin Virol 3:85-89. 
Lyons C.R., Orloff, G.J., and Cunningham, J.M. 
1992. Molecular cloning and functional expres- 
sion of an inducible nitric oxide synthase from a 
murine macrophage cell line. / Biol Chem 
267:6370-6374. 
GENETIC ANALYSIS OF NUCLEOCYTOPLASMIC TRANSPORT 
Laura I. Davis, Ph.D., Assistant Investigator 
Research in Dr. Davis's laboratory is aimed at un- 
derstanding how macromolecular transport across 
the nuclear envelope is controlled. The populations 
of RNA and protein found in the nucleus and cyto- 
plasm are very different. Newly synthesized mRNA, 
for example, is normally fully processed before 
moving into the cytoplasm. Similarly, only proteins 
containing specific signals are imported into the nu- 
cleus. Recently it has become clear that some media- 
tors of the signal transduction pathway exert their 
effect on transcription by modifying cytoplasmic 
transcription factors so as to allow their entry into 
the nucleus. Thus nucleocytoplasmic transport is an 
important regulatory point in the control of gene 
expression. 
Transport proceeds through large proteinaceous 
channels called nuclear pore complexes. These 
channels have an overall diameter of ~ 1 20 nm and 
have been estimated to contain up to 200 different 
polypeptides. It is likely that some pore proteins 
function to define the specificity of transport, 
whereas others carry out the actual translocation 
step. Among the few known components of the nu- 
clear pore complex is a family of polypeptides. 
42 
