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C-myc-induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent.

Publication ,  Journal Article
Trudel, M; Lanoix, J; Barisoni, L; Blouin, MJ; Desforges, M; L'Italien, C; D'Agati, V
Published in: J Exp Med
December 1, 1997

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.

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Published In

J Exp Med

DOI

ISSN

0022-1007

Publication Date

December 1, 1997

Volume

186

Issue

11

Start / End Page

1873 / 1884

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transgenes
  • Recombinant Fusion Proteins
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-bcl-2
  • Polycystic Kidney, Autosomal Dominant
  • Phenotype
  • Organ Specificity
  • Mice, Transgenic
  • Mice, Knockout
 

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Trudel, M., Lanoix, J., Barisoni, L., Blouin, M. J., Desforges, M., L’Italien, C., & D’Agati, V. (1997). C-myc-induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent. J Exp Med, 186(11), 1873–1884. https://doi.org/10.1084/jem.186.11.1873
Trudel, M., J. Lanoix, L. Barisoni, M. J. Blouin, M. Desforges, C. L’Italien, and V. D’Agati. “C-myc-induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent.J Exp Med 186, no. 11 (December 1, 1997): 1873–84. https://doi.org/10.1084/jem.186.11.1873.
Trudel M, Lanoix J, Barisoni L, Blouin MJ, Desforges M, L’Italien C, et al. C-myc-induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent. J Exp Med. 1997 Dec 1;186(11):1873–84.
Trudel, M., et al. “C-myc-induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent.J Exp Med, vol. 186, no. 11, Dec. 1997, pp. 1873–84. Pubmed, doi:10.1084/jem.186.11.1873.
Trudel M, Lanoix J, Barisoni L, Blouin MJ, Desforges M, L’Italien C, D’Agati V. C-myc-induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent. J Exp Med. 1997 Dec 1;186(11):1873–1884.

Published In

J Exp Med

DOI

ISSN

0022-1007

Publication Date

December 1, 1997

Volume

186

Issue

11

Start / End Page

1873 / 1884

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transgenes
  • Recombinant Fusion Proteins
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-bcl-2
  • Polycystic Kidney, Autosomal Dominant
  • Phenotype
  • Organ Specificity
  • Mice, Transgenic
  • Mice, Knockout