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Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy

ABSTRACT: Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by rapid progression to end-stage kidney disease (ESKD). Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). We used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. We found that inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocks disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency is associated with senescence enhancement and requires TGF-b functions. We further assessed efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice). We found that pharmacologic inhibition of WIP1 enzymatic activity in either telomerase mice with CG or in Tg26 mice promotes partial remission of proteinuria and ameliorates renal histopathologic features. Histological as well as high throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.

ORGANISM(S): Mus musculus

PROVIDER: GSE249878 | GEO | 2024/02/09

REPOSITORIES: GEO

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Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (ChIP-Seq)

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2015-04-23 | E-GEOD-60223 | biostudies-arrayexpress

Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (array)

Project description:Constitutively active MYC and reactivated telomerase often co-exist in cancers. While the reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with co-factors, confers several growth advantages to cancer cells. However, it is unclear which co-factors sustain elevated MYC activity in tumors . Here, we identify TERT, the catalytic subunit of telomerase, as a novel regulator of MYC stability in cancers. Binding of TERT to MYC stabilizes its levels on chromatin, contributing to either activation or repression of its target genes. Mechanistically, TERT regulates MYC ubiquitination and stability, and this effect of TERT is independent of its role on telomeres. Genetic inhibition and knocking out of TERT phenocopied the loss of MYC, resulting in reduced disease burden of early- and late-stage MYC-driven murine lymphomas. Conversly, the ectopic expression of TERT could substitute for reduced MYC in these functions. Finally we show that TERT null mice, unlike Terc null mice, show delayed onset of MYC induced lymphomagenesis. Accordingly, inhibiting TERT function in primary human leukemia cells blocked the expression of MYC targets, while Terc depletion had no effects . Based on our data, we conclude that the re-expression of TERT, a direct MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis. P493 cells were stably infected with the following viruses: pLKO shControl and pLKO shTERT.

2015-04-23 | E-GEOD-60175 | biostudies-arrayexpress

Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (ChIP-Seq)

2015-04-23 | GSE60223 | GEO

Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (array)

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2015-04-23 | GSE60175 | GEO

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2014-12-15 | E-GEOD-62973 | biostudies-arrayexpress

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2012-01-17 | E-GEOD-35045 | biostudies-arrayexpress

Evaluating the effects of cardiac telomerase re-activation after myocardial infarction in adult mice

2014-12-15 | GSE62973 | GEO

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2020-09-11 | GSE157815 | GEO

Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres

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2018-01-22 | GSE93869 | GEO

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2017-02-27 | GSE77265 | GEO

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