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

Trudel M, Lanoix J, Barisoni L, Blouin MJ, Desforges M, L'Italien C, D'Agati V - J. Exp. Med. (1997)

Bottom Line: No renal abnormalities were detected in 13 transgenic lines established, indicating that the PKD phenotype is dependent on functions specific to c-myc.All SBM offspring, irrespective of their p53 genotype, developed PKD with increased renal epithelial apoptotic index.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.

View Article: PubMed Central - PubMed

Affiliation: Institut de Recherches Cliniques de Montréal, Faculté de Médecine de l'Université de Montréal, Montréal, Québec, Canada H2W 1R7.

ABSTRACT
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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c-myc expression induces increased proliferation in transgenic SBM renal epithelial cells. (a) In situ hybridization for the c-myc transgene  shows high expression in the cystic renal epithelium of adult SBM mice (dark field optics, X112.5). (b) Proliferation analysis of SBM adult kidneys with  antibody MIB-1 reveals many positive cells lining the renal cysts. There is a tendency for positive nuclear staining to be clustered. MIB-1 immunostain,  periodic acid-Schiff counterstain, ×300.
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Figure 1: c-myc expression induces increased proliferation in transgenic SBM renal epithelial cells. (a) In situ hybridization for the c-myc transgene shows high expression in the cystic renal epithelium of adult SBM mice (dark field optics, X112.5). (b) Proliferation analysis of SBM adult kidneys with antibody MIB-1 reveals many positive cells lining the renal cysts. There is a tendency for positive nuclear staining to be clustered. MIB-1 immunostain, periodic acid-Schiff counterstain, ×300.

Mentions: To determine the site and cellular localization of c-myc expression within the adult kidneys, we examined normal and cystic SBM kidneys by in situ hybridization. A strong expression of the c-myc transgene was specifically localized to the SBM renal cystic epithelium as well as focal noncystic tubules (Fig. 1 a), with undetectable signal in adult controls. This overexpression of c-myc in the renal epithelium correlated with the development of hyperplasia and abnormal polarity in many of the cystic tubules.


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

Trudel M, Lanoix J, Barisoni L, Blouin MJ, Desforges M, L'Italien C, D'Agati V - J. Exp. Med. (1997)

c-myc expression induces increased proliferation in transgenic SBM renal epithelial cells. (a) In situ hybridization for the c-myc transgene  shows high expression in the cystic renal epithelium of adult SBM mice (dark field optics, X112.5). (b) Proliferation analysis of SBM adult kidneys with  antibody MIB-1 reveals many positive cells lining the renal cysts. There is a tendency for positive nuclear staining to be clustered. MIB-1 immunostain,  periodic acid-Schiff counterstain, ×300.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199149&req=5

Figure 1: c-myc expression induces increased proliferation in transgenic SBM renal epithelial cells. (a) In situ hybridization for the c-myc transgene shows high expression in the cystic renal epithelium of adult SBM mice (dark field optics, X112.5). (b) Proliferation analysis of SBM adult kidneys with antibody MIB-1 reveals many positive cells lining the renal cysts. There is a tendency for positive nuclear staining to be clustered. MIB-1 immunostain, periodic acid-Schiff counterstain, ×300.
Mentions: To determine the site and cellular localization of c-myc expression within the adult kidneys, we examined normal and cystic SBM kidneys by in situ hybridization. A strong expression of the c-myc transgene was specifically localized to the SBM renal cystic epithelium as well as focal noncystic tubules (Fig. 1 a), with undetectable signal in adult controls. This overexpression of c-myc in the renal epithelium correlated with the development of hyperplasia and abnormal polarity in many of the cystic tubules.

Bottom Line: No renal abnormalities were detected in 13 transgenic lines established, indicating that the PKD phenotype is dependent on functions specific to c-myc.All SBM offspring, irrespective of their p53 genotype, developed PKD with increased renal epithelial apoptotic index.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.

View Article: PubMed Central - PubMed

Affiliation: Institut de Recherches Cliniques de Montréal, Faculté de Médecine de l'Université de Montréal, Montréal, Québec, Canada H2W 1R7.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus