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Development of an improved inhibitor of Lats Kinases to promote regeneration of mammalian organs

ABSTRACT: To confirm that treatment with TDI‑011536 activates Yap in vivo, we collected liver and heart tissue for RNA sequencing four hours after IP injection at 200 mg/kg

ORGANISM(S): Mus musculus

PROVIDER: GSE196322 | GEO | 2022/07/06

REPOSITORIES: GEO

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Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs.

Project description:The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular signals can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily postmitotic and aids regeneration in mammals. In the present study, we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of Yap target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies.

| S-EPMC9282237 | biostudies-literature

Development of an improved inhibitor of Lats Kinases to promote regeneration of mammalian organs

Project description:Development of an improved inhibitor of Lats Kinases to promote regeneration of mammalian organs

| PRJNA804393 | ENA

Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues.

Project description:Hippo signaling is an evolutionarily conserved pathway that restricts growth and regeneration predominantly by suppressing the activity of the transcriptional coactivator Yap. Using a high-throughput phenotypic screen, we identified a potent and non-toxic activator of Yap. In vitro kinase assays show that the compound acts as an ATP-competitive inhibitor of Lats kinases-the core enzymes in Hippo signaling. The substance prevents Yap phosphorylation and induces proliferation of supporting cells in the murine inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the inhibitor reversibly activates the expression of transcriptional Yap targets: upon withdrawal, a subset of supporting-cell progeny exits the cell cycle and upregulates genes characteristic of sensory hair cells. Our results suggest that the pharmacological inhibition of Lats kinases may promote initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear.

| S-EPMC8149661 | biostudies-literature

Downregulation of LATS kinases alters p53 to promote cell migration

Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-?B subunit. Moreover, it partly shifts p53âs conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator. MCF10A cells transfected with siRNA against LATS1/2 alone, p53 alone or LATS1/2 and p53 together. Two independent MCF10A batches provided biological replicates

2015-12-11 | E-GEOD-74493 | biostudies-arrayexpress

Down-regulation of LATS kinases alters p53 to promote cell migration.

Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in nontransformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53's conformation and transcriptional output toward a state resembling cancer-associated p53 mutants and endows p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently down-regulated in breast cancer; we propose that such down-regulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.

| S-EPMC4691886 | biostudies-literature

Downregulation of LATS kinases alters p53 to promote cell migration

Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-?B subunit. Moreover, it partly shifts p53’s conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.

2015-12-11 | GSE74493 | GEO

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Project description:Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

| PRJNA624890 | ENA

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Project description:We report on the gene expression changes associated with Lats1/2 inhibition in supporting cells of the vestibular inner ear sensory epithelium

2020-04-13 | GSE148528 | GEO

Downregulation of LATS kinases alters p53 to promote cell migration

Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53’s conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.

2018-10-25 | PXD003120 | Pride

Effects of low and high doses of bisphenol A on mouse liver transcriptome

Project description:Bisphenol A (BPA) is used in the plastic industry as the monomer of polycarbonates and epoxy resins. Heat and changes in pH conditions lead to its leakage from the plastics in which it is incorporated. This largely contributes to the widespread exposure of the general population to this environmental contaminant. The exposure levels in humans are likely below the Tolerable Daily Intake (TDI: 50 µg/kg/day) and well below the No Observable Adverse Effect Level (NOAEL: 5000 µg/kg/day) defined from reprotoxicity studies. However, several studies suggest that BPA could induce deleterious effects specifically at low, environmentally relevant, doses. BPA has been described as an endocrine disruptor with estrogenic activity. Recently, it has been shown that BPA exposure has an impact on metabolic functions including stimulation of adipogenesis and of insulin production by the pancreas. Here, we investigated the effects of oral exposure to low (TDI) and high (NOAEL) doses of BPA on mouse liver transcriptome. Liver gene expression was measured from CD-1 mice (6 mice/group) exposed for 28 days to bisphenol A at doses 0 (controls), 50 (TDI or low dose) or 5000 µg/kg/day (NOAEL or high dose) via food contamination.

2011-09-20 | E-GEOD-26728 | biostudies-arrayexpress

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