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The Anti-Aging and Tumor Suppressor Protein Klotho Affects Signaling Pathwaysin a Human Oligodendroglioma Cell Line

ABSTRACT: Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here we examined the effects of Klotho on MO3.13, a human oligodendroglioma cell line in order to determine the potential role of Klotho as a tumor suppressor. We show that exogenous Klotho affects the ERK and Akt signaling pathways and decreases the proliferative abilities of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80% of the differentially expressed genes being downregulated. Using gene set enrichment analysis we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain malignancies. 6 Samples

ORGANISM(S): Homo sapiens

SUBMITTER: Chen CD

PROVIDER: S-ECPF-GEOD-51536 | biostudies-other | 2015 Jan

REPOSITORIES: biostudies-other

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The Anti-Aging and Tumor Suppressor Protein Klotho Affects Signaling Pathwaysin a Human Oligodendroglioma Cell Line

Project description:Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here we examined the effects of Klotho on MO3.13, a human oligodendroglioma cell line in order to determine the potential role of Klotho as a tumor suppressor. We show that exogenous Klotho affects the ERK and Akt signaling pathways and decreases the proliferative abilities of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80% of the differentially expressed genes being downregulated. Using gene set enrichment analysis we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain malignancies. 6 Samples

2014-06-09 | E-GEOD-51536 | biostudies-arrayexpress

The Anti-Aging and Tumor Suppressor Protein Klotho Affects Signaling Pathwaysin a Human Oligodendroglioma Cell Line

2014-06-09 | GSE51536 | GEO

The anti-aging and tumor suppressor protein Klotho enhances differentiation of a human oligodendrocytic hybrid cell line.

Project description:Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats, and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here, we examined the signaling pathways induced by Klotho in MO3.13, a human oligodendrocytic hybrid cell line. We show that exogenous Klotho affects the ERK and Akt signaling pathways, decreases the proliferative abilities and enhances differentiation of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80 % of the differentially expressed genes being downregulated. Using gene set enrichment analysis, we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging, and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain and other malignancies.

| S-EPMC5154549 | biostudies-literature

The anti-aging protein Klotho affects early postnatal myogenesis by downregulating Jmjd3 and the canonical Wnt pathway.

Project description:Modulating the number of muscle stems cells, called satellite cells, during early postnatal development produces long-term effects on muscle growth. We tested the hypothesis that high expression levels of the anti-aging protein Klotho in early postnatal myogenesis increase satellite cell numbers by influencing the epigenetic regulation of genes that regulate myogenesis. Our findings show that elevated klotho expression caused a transient increase in satellite cell numbers and slowed muscle fiber growth, followed by a period of accelerated muscle growth that leads to larger fibers. Klotho also transcriptionally downregulated the H3K27 demethylase Jmjd3, leading to increased H3K27 methylation and decreased expression of genes in the canonical Wnt pathway, which was associated with a delay in muscle differentiation. In addition, Klotho stimulation and Jmjd3 downregulation produced similar but not additive reductions in the expression of Wnt4, Wnt9a, and Wnt10a in myogenic cells, indicating that inhibition occurred through a common pathway. Together, our results identify a novel pathway through which Klotho influences myogenesis by reducing the expression of Jmjd3, leading to reductions in the expression of Wnt genes and inhibition of canonical Wnt signaling.

| S-EPMC9007106 | biostudies-literature

A polymorphism in the tumor suppressor p53 affects aging and longevity in mouse models.

Project description:Tumor suppressor p53 prevents early death due to cancer development. However, the role of p53 in aging process and longevity has not been well-established. In humans, single nucleotide polymorphism (SNP) with either arginine (R72) or proline (P72) at codon 72 influences p53 activity; the P72 allele has a weaker p53 activity and function in tumor suppression. Here, employing a mouse model with knock-in of human TP53 gene carrying codon 72 SNP, we found that despite increased cancer risk, P72 mice that escape tumor development display a longer lifespan than R72 mice. Further, P72 mice have a delayed development of aging-associated phenotypes compared with R72 mice. Mechanistically, P72 mice can better retain the self-renewal function of stem/progenitor cells compared with R72 mice during aging. This study provides direct genetic evidence demonstrating that p53 codon 72 SNP directly impacts aging and longevity, which supports a role of p53 in regulation of longevity.

| S-EPMC5906094 | biostudies-literature

The anti-aging protein Klotho affects early postnatal myogenesis by down-regulating Jmjd3 and the canonical Wnt pathway

Project description:Modulating the number of muscle stems cells, called satellite cells, during early postnatal development produces long-term effects on muscle growth. We tested the hypothesis that high expression levels of the anti-aging protein Klotho in early postnatal myogenesis increase satellite cell numbers by influencing the epigenetic regulation of genes that regulate myogenesis. Our findings show that elevated klotho expression caused a transient increase in satellite cell numbers and slowed muscle fiber growth, followed by a period of accelerated muscle growth that resulted in larger fibers. Klotho also transcriptionally down-regulated the H3K27 demethylase Jmjd3, increased H3K27 methylation and decreased expression of genes in the canonical Wnt pathway, which was associated with a significant delay in muscle differentiation. In addition, Klotho stimulation and subsequent Jmjd3 down-regulation produced similar but not additive reductions in the expression of Wnt4, Wnt9a and Wnt10a in myogenic cells, indicating that inhibition occurred through a common pathway. Together, our results identify a novel pathway through which Klotho influences myogenesis by reducing expression of Jmjd3, leading to reductions in the expression of Wnt genes and inhibition of canonical Wnt signaling.

2022-04-20 | GSE189109 | GEO

Regulation of S-formylglutathione hydrolase by the anti-aging gene klotho.

Project description:Klotho is an aging-suppressor gene. The purpose of this study is to investigate the binding sites (receptors) and function of short-form Klotho (Skl). We showed that Skl physically bound to multiple proteins. We found physical and functional interactions between Skl and S-formylglutathione hydrolase (FGH), a key enzyme in the generation of the major cellular anti-oxidant GSH, using co-immunoprecipitation-coupled mass spectrometry. We further confirmed the colocalization of Skl and FGH around the nucleus in kidney cells using immunofluorescent staining. Skl positively regulated FGH gene expression via Kid3 transcription factor. Overexpression of Skl increased FGH mRNA and protein expression while silencing of Skl attenuated FGH mRNA and protein expression. Klotho gene mutation suppressed FGH expression in red blood cells and kidneys resulting in anemia and kidney damage in mice. Overexpression of Skl increased total GSH production and the GSH/GSSG ratio, an index of anti-oxidant capacity, leading to a decrease in intracellular H2O2 and superoxide levels. The antioxidant activity of Skl was eliminated by silencing of FGH, indicating that Skl increased GSH via FGH. Interestingly, Skl directly interacted with FGH and regulated its function. Site-directed mutagenesis of the N-glycan-modified residues in Skl abolished its antioxidant activity, suggesting that these N-glycan moieties are important features that interact with FGH. Specific mutation of Asp to Ala at site 285 resulted in a loss of anti-oxidant activity of Skl, suggesting that N-glycosylation at site 285 is the key mechanism that determines Skl activity. Therefore, this study demonstrates, for the first time, that Skl regulates anti-oxidant GSH generation via interaction with FGH through N-glycosylation.

| S-EPMC5687603 | biostudies-literature

Cytokine-induced release of ceramide-enriched exosomes as a mediator of cell death signaling in an oligodendroglioma cell line.

Project description:Th1 pro-inflammatory cytokines, i.e., TNF-? and IFN-?, in combination are known to induce cell death in several cell types, including oligodendrocytes, but the mechanism of their synergistic cytotoxicity is unclear. Although ceramide (Cer) has been implicated in cytokine- and stress-induced cell death, its intracellular levels alone cannot explain cytokine synergy. We considered the possibility that Cer released as part of extracellular vesicles may contribute to cytokine-induced synergistic cell death. Using a human oligodendroglioma (HOG) cell line as a model, here we show that exosomes derived from TNF-?-treated "donor" cells, while being mildly toxic to fresh cultures (similar to individual cytokines), induce enhanced cell death when added to IFN-?-primed target cultures in a fashion resembling the effect of cytokine combination. Further, the sphingolipid profiles of secreted exosomes, as determined by HPLC-MS/MS, revealed that the treatment with the cytokines time-dependently induced the formation and exosomal release, in particular of C16-, C24-, and C24:1-Cer species; C16-, C24-, and C24:1-dihydroCer species; and C16-, C24-, and C24:1-SM species. Finally, exogenous C6-Cer or C16-Cer mimicked and enhanced the cytotoxic effects of the cytokines upon HOG cells, thereby supporting the cell death-signaling role of extracellular Cer.

| S-EPMC5087870 | biostudies-other

Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions.

Project description:Control of phosphate metabolism is crucial to regulate aging in mammals. Klotho is a well-known anti-aging factor that regulates phosphate metabolism: mice mutant or deficient in Klotho exhibit phenotypes resembling human aging. Here we show that ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is required for Klotho expression under phosphate overload conditions. Loss-of-function Enpp1 ttw/ttw mice under phosphate overload conditions exhibited phenotypes resembling human aging and Klotho mutants, such as short life span, arteriosclerosis and osteoporosis, with elevated serum 1,25(OH)2D3 levels. Enpp1 ttw/ttw mice also exhibited significantly reduced renal Klotho expression under phosphate overload conditions, and aging phenotypes in these mice were rescued by Klotho overexpression, a low vitamin D diet or vitamin D receptor knockout. These findings indicate that Enpp1 plays a crucial role in regulating aging via Klotho expression under phosphate overload conditions.

| S-EPMC5552841 | biostudies-other

Klotho suppresses tumor progression via inhibiting PI3K/Akt/GSK3?/Snail signaling in renal cell carcinoma.

Project description:Klotho is an anti-aging protein predominantly expressed in renal tubular epithelial cells. Although Klotho was recently identified as a tumor suppressor gene in a variety of cancers, the potential role and molecular events for Klotho in renal cell carcinoma (RCC) remain obscure. In the present study, immunohistochemical staining in tissue microarrays containing 125 RCC samples showed that intratumoral Klotho levels were negatively correlated with tumor size, TNM stage and nuclear grade. The overall survival rate of RCC patients with high Klotho expression was significantly higher than that of patients with low Klotho expression. Functional analysis after gain and loss of Klotho expression revealed that Klotho blunted epithelial-mesenchymal transition and cellular migration and invasion in RCC. Also, no alteration of ?-2,6-sialidase activity was found after Klotho overexpression in RCC. The molecular signals for this phenomenon involved the Klotho-mediated inhibition of PI3K/Akt/GSK3?/Snail pathway. Importantly, compared to localized RCC tissues, advanced RCC tissues exhibited low Klotho expression accompanied with high pAkt and Snail expression. These results indicate Klotho acts as a tumor suppressor by inhibiting PI3K/Akt/GSK3?/Snail signaling, thus suppressing epithelial-mesenchymal transition and tumor migration and invasion during RCC progression. As a result, Klotho might be used as a potential therapy for advanced RCC.

| S-EPMC7657207 | biostudies-literature

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