The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/12/1873/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 11, December 1, 1997 1873-1884

Articles

C-MYC–induced Apoptosis in Polycystic Kidney Disease Is Bcl-2 and p53 Independent

Marie Trudel*, Jacqueline Lanoix*, Laura Barisoni{ddagger}, Marie-José Blouin*, Marc Desforges*, Catherine L'Italien*, and Vivette D'Agati{ddagger}

From the * Institut de Recherches Cliniques de Montréal, Faculté de Médecine de l'Université de Montréal, Montréal, Québec, Canada H2W 1R7; and {ddagger} Department of Pathology, College of Physicians and Surgeons of Columbia University, New York 10032

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)-{alpha} 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.

Address correspondence to Marie Trudel, Ph.D., Institut de Recherches Cliniques de Montréal, 110, avenue des Pins Ouest, Montréal, Québec, Canada H2W 1R7. Phone: (514) 987-5712; FAX: (514) 987-5585.

1Abbreviations used in this paper: ADPKD, autosomal dominant polycystic kidney disease; PKD, polycystic kidney disease.

We are very grateful to Dr. M. Aubry for helpful discussions and Dr. J. Deschamps for the gift of the c-fos gene. We thank C. Lagacé, J.C. Dunn, K. Butterfield, V. Ouellet, and N. Chrétien for technical assistance. This work was supported by grants from The Kidney Foundation of Canada (M. Trudel), the Medical Research Council of Canada (M. Trudel), the National Institutes of Health (no. DK44864, M. Trudel), Coopération Québec/\x83 tats-Unis (M. Trudel), M.Trudel is a chercheur-boursier of Fonds de la Recherche en Santé du Québec.


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