of mdr and mdr-like genes is critical for drug recog- 
nition and transport. 
Construction of Model Substrates for P-gp 
The high degree of hydrophobicity and the pres- 
ence of a positive charge at neutral pH are two major 
common characteristics of MDR drugs. In an effort 
to identify the chemical determinants of MDR drugs 
that are essential for recognition by P-gp, simple li- 
pophilic cations such as tetraphenylphosphonium 
(TPP^) and tetraphenylarsonium (TPA^) were 
tested and shown to be transported by P-gp. The 
progressive replacement of phenyl groups or intro- 
duction of long aliphatic side chains was shown to 
reduce their affinity for P-gp. It appears from these 
preliminary studies that the ability of the phenyl 
groups to delocalize the charge in the molecule is 
an important determinant for both cytotoxicity and 
P-gp recognition. By opposition to known MDR 
drugs, the relatively simple structure of these com- 
pounds renders them very easily amenable to exten- 
sive chemical modification, and Dr. Gros and his 
colleagues have started to analyze additional deriva- 
tives of TPP+. 
Complementation of the Yeast mrfrHomologue 
STE6 by Its Mammalian Counterpart 
The yeast Saccharomyces cerevisiae homologue 
of mdr, STE6, is the membrane transporter mediat- 
ing export of the a-factor mating peptide. Yeast 
MATa cells carrying an ste6 deletion produce no 
extracellular a-factor and therefore are defective in 
mating. Expression of a full-length cDNA clone for 
mouse mdr3 in a yeast ste6 deletion strain was 
shown to restore the ability to export a-factor and to 
mate. A mutation (a Ser Phe substitution at posi- 
tion 939 in TMl 1) known to affect the activity of 
the mdr3 gene product abolished its ability to com- 
plement the yeast ste6 deletion. These experiments 
show that P-gp can transport peptides in yeast cells 
and perhaps also in normal mouse tissues. In addi- 
tion, the functional expression of P-gp in yeast cells 
should 1) greatly facilitate the structure/function 
analysis of P-gp by site-directed mutagenesis, in- 
cluding the analysis of possible intramolecular in- 
teraction in P-gp by selection of second-site muta- 
tions; 2) permit production of large amounts of P-gp 
for functional and structural studies; and 3) enable 
the design and testing of a-factor peptide analogues 
as potential blockers of P-gp function. 
Other Activities 
The mouse mutation splotch (Sp) blocks closure 
of the neural tube during neurogenesis, resulting in 
spina bifida and exencephaly, two common birth 
defects in humans. It has recently been shown that 
the Sp mutation {Sp^") is caused by a deletion in the 
paired box of the Pax- 3 gene, a member of a new 
family of transcription factors {Pax) expressed 
exclusively during embryogenesis. This deletion 
also removes the entire homeodomain and trans- 
activating domain of Pax-3- These results identify a 
key role for Pax-3 in the normal and perhaps abnor- 
mal development of the nervous system in mam- 
mals. 
Dr. Gros is Associate Professor of Biochemistry 
in the McGill Cancer Center and Center for the 
Study of Host Resistance, McGill University, 
Montreal. 
Articles 
Epstein, D.J., Vekemans, M., and Gros, P. 1991. 
splotch (Sp^^) , a mutation affecting development 
of the mouse neural tube, shows a deletion within 
the paired homeodomain of Pax-3- Cell 
llA. 
Gros, P., Dhir, R., Croop, J., and Talbot, F. 1991. A 
single amino acid substitution strongly modulates 
the activity and substrate specificity of the mouse 
mdrl and mdr3 drug efflux pumps. Proc Natl 
Acad Sci USA 88:7289-7293. 
Gros, P., Talbot, P., Tang-Wai, D., Bibi, E., and Ka- 
back, H.R. 1992. Lipophilic cations: a group of 
model substrates for the multidrug-resistance 
transporter. Biochemistry 31:1992-1998. 
Raymond, M., Gros, P., Whiteway, M., and Thomas, 
D.Y. 1992. Functional complementation of the 
yeast ste6 by a mammalian multidrug resistance 
mdrgcne. Science 256:232-234. 
Shustik, C, Groulx, N., and Gros, P. 1991 . Analysis 
of multidrug resistance (MDR-1) gene expression 
in chronic lymphocytic leukaemia (CLL). Br f 
Haematol 79:50-56. 
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