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J. Exp. Med.,
Volume 186, Number 11, December 1, 1997 1873-1884
By
From the * Institut de Recherches Cliniques de Montréal, Faculté de Médecine de l'Université de
Montréal, Montréal, Québec, Canada H2W 1R7; and The SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) induced by
the dysregulated expression of c-myc in renal tissue. In situ hybridization analysis demonstrated
intense signal for the c-myc transgene overlying tubular cystic epithelium in SBM mice. Renal
proliferation index in SBM kidneys was 10-fold increased over nontransgenic controls correlating with the presence of epithelial hyperplasia. The specificity of c-myc for the proliferative potential of epithelial cells was demonstrated by substitution of c-myc with the proto-oncogene c-fos or the transforming growth factor (TGF)- Department of Pathology, College of
Physicians and Surgeons of Columbia University, New York 10032
within the same construct. No renal abnormalities were detected in 13 transgenic lines established, indicating that the PKD phenotype
is dependent on functions specific to c-myc. We also investigated another well characterized
function of c-myc, the regulation of apoptosis through pathways involving p53 and members
of the bcl-2 family, which induce and inhibit apoptosis, respectively. The SBM kidney tissues,
which overexpress c-myc, displayed a markedly elevated (10-100-fold) apoptotic index. However, no significant difference in bcl-2, bax, or p53 expression was observed in SBM kidney
compared with controls. Direct proof that the heightened renal cellular apoptosis in PKD is not
occurring through p53 was obtained by successive matings between SBM and p53
/ mice. All
SBM offspring, irrespective of their p53 genotype, developed PKD with increased renal epithelial apoptotic index. In addition, overexpression of both bcl-2 and c-myc in double transgenic mice (SBB+/SBM+) also produced a similar PKD phenotype with a high apoptotic rate,
showing that c-myc can bypass bcl-2 in vivo. Thus, the in vivo c-myc apoptotic pathway in
SBM mice occurs through a p53- and bcl-2-independent mechanism. We conclude that the
pathogenesis of PKD is c-myc specific and involves a critical imbalance between the opposing
processes of cell proliferation and apoptosis.
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