c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

Trudel, Marie

doi:10.15586/codon.pkd.2015.ch10

Cited by 18 publications

(23 citation statements)

References 112 publications

(108 reference statements)

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“…To examine BicC role(s) in the Malpighian tubule, RNA-protein (RNP) complexes were immunoprecipitated from extracts of Malpighian tubules from wild-type flies with either the BicC antiserum or a non-immune serum. The content of d-myc RNA was specifically analyzed in the BicC-associated RNA pool, because of the important role c-Myc plays in kidney cystogenesis in mammals [ 38 , 39 , 40 , 41 ]. Unlike the non-immune control, an RT-PCR product for the d-myc mRNA was specifically obtained from BicC RNP immunoprecipitates ( Fig 5A ).…”

Section: Resultsmentioning

confidence: 99%

Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila

et al. 2017

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Progressive cystic kidney degeneration underlies diverse renal diseases, including the most common cause of kidney failure, autosomal dominant Polycystic Kidney Disease (PKD). Genetic analyses of patients and animal models have identified several key drivers of this disease. The precise molecular and cellular changes underlying cystogenesis remain, however, elusive. Drosophila mutants lacking the translational regulator Bicaudal C (BicC, the fly ortholog of vertebrate BICC1 implicated in renal cystogenesis) exhibited progressive cystic degeneration of the renal tubules (so called “Malpighian” tubules) and reduced renal function. The BicC protein was shown to bind to Drosophila (d-) myc mRNA in tubules. Elevation of d-Myc protein levels was a cause of tubular degeneration in BicC mutants. Activation of the Target of Rapamycin (TOR) kinase pathway, another common feature of PKD, was found in BicC mutant flies. Rapamycin administration substantially reduced the cystic phenotype in flies. We present new mechanistic insight on BicC function and propose that Drosophila may serve as a genetically tractable model for dissecting the evolutionarily-conserved molecular mechanisms of renal cystogenesis.

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Section: Resultsmentioning

confidence: 99%

Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila

et al. 2017

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“…Interestingly, it has long been appreciated that overexpression of c-Myc in mouse kidneys can induce tubular cysts (Trudel et al 1991). Although activation of c-Myc has been observed in several PKD animal models (Trudel 2015), it was unclear whether c-Myc contributes to ADPKD pathogenesis. Our genetic analysis demonstrates that as a direct target gene of YAP, c-Myc not only is essential for Sav1 mutant kidney and liver phenotypes but also functions as a critical mediator of cystogenesis in Pkd1 mutant kidneys.…”

Section: Discussionmentioning

confidence: 99%

A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease

et al. 2018

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Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in or and affects one in 500-1000 humans. Limited treatment is currently available for ADPKD. Here we identify the Hippo signaling effector YAP and its transcriptional target, c-Myc, as promoters of cystic kidney pathogenesis. While transgenic overexpression of YAP promotes proliferation and tubule dilation in mouse kidneys, loss of YAP/TAZ or c-Myc suppresses cystogenesis in a mouse ADPKD model resulting from deficiency. Through a comprehensive kinase inhibitor screen based on a novel three-dimensional (3D) culture of mutant mouse kidney cells, we identified a signaling pathway involving the RhoGEF (guanine nucleotide exchange factor) LARG, the small GTPase RhoA, and the RhoA effector Rho-associated kinase (ROCK) as a critical signaling module between PKD1 and YAP. Further corroborating its physiological importance, inhibition of RhoA signaling suppresses cystogenesis in 3D culture of mutant kidney cells as well as mutant mouse kidneys in vivo. Taken together, our findings implicate the RhoA-YAP-c-Myc signaling axis as a critical mediator and potential drug target in ADPKD.

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“…In one scenario, a complex of both polycystins could act as a mechanoreceptor signaling via Ca 2+ influx through PC-2, a TRP channel, after fluid flow registration by PC-1 [ 7 ]. On the basis of recent results, the polycystin complex is associated with various cell signaling pathways (c-Myc, Wnt/β-catenin, hedgehog) [ 8 – 10 ]. Looking for new prognostic biomarkers as well as therapeutic targets and procedures is the constant ongoing approach [ 11 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Bilineal inheritance of pathogenic PKD1 and PKD2 variants in a Czech family with autosomal dominant polycystic kidney disease – a case report

et al. 2018

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BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder, leading to end stage renal failure and kidney transplantation in its most serious form. The severity of the disease’s manifestation depends on the genetic determination of ADPKD. The huge variability of different phenotypes (even within a single family) is not only modulated by the two main ADPKD genes (PKD1 and PKD2) but also by modifier genes and the whole genetic background.Case presentationThis is a report of an ADPKD family with co-inheritance of PKD1 and PKD2 pathogenic variants. The proband, with an extremely serious manifestation of ADPKD (the man was diagnosed in early childhood, and with end stage renal disease aged 23), underwent genetic analysis of PKD1 and PKD2, which revealed the presence of pathogenic mutations in both of these genes. The missense PKD2 mutation p.Arg420Gly came from the proband’s father, with a mild ADPKD phenotype. The same mutation of the PKD2 gene and similar mild disease presentation were found in the proband’s aunt (father’s sister) and her son. The nonsense mutation p.Gln2196* within the PKD1 gene was probably inherited from the proband’s mother, who died at the age of 45. It was only discovered post mortem, that the real cause of her death was kidney failure as a consequence of untreated ADPKD. Unfortunately, neither the DNA of the proband’s mother nor the DNA of any other family members from this side of the pedigree were available for further examination. The proband underwent successful cadaveric kidney transplantation at the age of 24, and this replacement therapy lasted for the next 15 years.ConclusionsHere, we present a first case of bilineal ADPKD inheritance in the Czech Republic. This report highlights the significant role of modifier genes in genetic determination of ADPKD, especially in connection with seriously deteriorated disease phenotypes. In our case, the modifying role is probably mediated by the PKD2 gene.

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c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

Cited by 18 publications

References 112 publications

Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila

Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila

A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease

Bilineal inheritance of pathogenic PKD1 and PKD2 variants in a Czech family with autosomal dominant polycystic kidney disease – a case report

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