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

• DOI: 10.1084/jem.186.11.1873
• Publication Date: 2002-07-26T16:49:30Z
• Authors: Marie Trudel; Jacqueline Lanoix; Laura Barisoni; Marie-José Blouin; Marc Desforges; Catherine L'Italien; Vivette D'Agati
• Keywords: Mice, Knockout; 0301 basic medicine; Hyperplasia; Genes, myc; Gene Expression; Apoptosis; Epithelial Cells; Mice, Transgenic; Genes, p53; Polycystic Kidney, Autosomal Dominant; Proto-Oncogene Proteins c-myc; Disease Models, Animal; Mice; 03 medical and health sciences; Kidney Tubules; Phenotype; Proto-Oncogene Proteins c-bcl-2; Organ Specificity; Genes, Synthetic; Animals; Cell Division; Crosses, Genetic

The SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) induced by the dysregulated expression c-myc in renal tissue. In situ hybridization analysis demonstrated intense signal for transgene overlying tubular cystic epithelium mice. Renal proliferation index kidneys was 10-fold increased over nontransgenic controls correlating with presence epithelial hyperplasia. specificity proliferative potential cells substitution proto-oncogene c-fos or transforming growth factor (TGF)-α within same construct. No abnormalities were detected 13 lines established, indicating that PKD phenotype dependent on functions specific to c-myc. We also investigated another well characterized function c-myc, regulation apoptosis through pathways involving p53 and members bcl-2 family, which induce inhibit apoptosis, respectively. tissues, overexpress displayed markedly elevated (10–100-fold) apoptotic index. However, no significant difference bcl-2, bax, observed compared controls. Direct proof heightened cellular not occurring obtained successive matings between p53−/− All offspring, irrespective their genotype, developed addition, overexpression both double mice (SBB+/SBM+) produced similar high rate, showing can bypass vivo. Thus, vivo pathway occurs p53- bcl-2–independent mechanism. conclude pathogenesis involves critical imbalance opposing processes cell apoptosis.