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Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression

ABSTRACT: Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression

PROVIDER: PRJNA1237769 | ENA |

REPOSITORIES: ENA

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Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression

Project description:Skeletal muscle wasting results from numerous conditions, such as sarcopenia, glucocorticoid therapy or intensive care. It prevents independent living in the elderly, predisposes to secondary diseases, and ultimately reduces lifespan. There is no approved drug therapy and the major causative mechanisms are not fully understood. Dual specificity phosphatase 22 (DUSP22) is a pleiotropic signaling molecule that plays important roles in immunity and cancer. However, the role of DUSP22 in skeletal muscle wasting is unknown. In this study, DUSP22 was found to be upregulated in sarcopenia patients and models of skeletal muscle wasting. DUSP22 knockdown or pharmacological inhibition with BML-260 prevented multiple forms of muscle wasting. Mechanistically, targeting DUSP22 suppressed FOXO3a, a master regulator of skeletal muscle wasting, via downregulation of the stress-activated kinase JNK, which occurred independently of aberrant Akt activation. DUSP22 targeting was also effective in human skeletal muscle cells undergoing atrophy. In conclusion, phosphatase DUSP22 is a novel target for preventing skeletal muscle wasting and BML-260 is a therapeutically effective small molecule inhibitor. The DUSP22-JNK-FOXO3a axis could be exploited to treat sarcopenia or related aging disorders.

2025-03-25 | GSE292258 | GEO

Transcriptome profiling of brown adipocytes treated with BML-260, DMSO or ISO for revealing the BML-260 mechanism

Project description:To explore BML-260 how to increase thermogenesis, we treated brown adipocytes with BML-260 and DMSO for 1 day or 3 days after seven days' differenciation. Meanwhile, we also set ISO (isoproterenol)-treated brown adipocytes as positive control. We found that BML-260 treatment led to very significant upregulation of genes involved in oxidative phosphorylation, fatty acid beta-oxidation, and mitochondrial function.When compared to cells treated with ISO, although both showed significant upregulation of UCP1, BML-260-treated cells showed a rather distinct gene profile when compared to ISO-treated cells. This work provides evidences that BML-260 can also exert a JSP-1-independent effect in activating UCP1 and thermogenesis in adipocytes, and be potentially applied to treat obesity.

2019-04-16 | GSE129791 | GEO

Transcriptome profiling of mouse subcutaneous white adipose tissue treated with BML-260

Project description:To explore BML-260 how to increase thermogenesis, we examined the effect of BML-260 by direct in situ injection into the subcutaneous white adipose depot. Three days after a single injection, mice were dissected and subcutaneous adipose tissues were obtained for RNA extraction. we noticed that BML-260 treatment resulted in a very significant upregulation of genes involved in thermogenesis. And gene signatures of muscle cell differentiation, muscle structure development, regulation of muscle system process were among the most enriched GO terms. Our work provides evidences that BML-260 can also exert a JSP-1-independent effect in activating UCP1 and thermogenesis in adipocytes, and be potentially applied to treat obesity.

2019-04-14 | GSE129771 | GEO

Transcriptome profiling of brown adipocytes treated with BML-260, DMSO or ISO for revealing the BML-260 mechanism

Project description:Transcriptome profiling of brown adipocytes treated with BML-260, DMSO or ISO for revealing the BML-260 mechanism

| PRJNA532837 | ENA

Transcriptome profiling of mouse subcutaneous white adipose tissue treated with BML-260

Project description:Transcriptome profiling of mouse subcutaneous white adipose tissue treated with BML-260

| PRJNA532721 | ENA

BML

Project description:bml SEQ

| PRJEB33313 | ENA

Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements

Project description:Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. While ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bisulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. Additionally, DUSP22-rearranged ALCLs minimally expressed PD-L1 compared to other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like, immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.

2018-08-08 | GSE118238 | GEO

RNA sequencing analysis of wild-type and BML-210 treated breast cancer EO771

Project description:We investigated the molecular mechanism by which BML-210 enhanced the response of breast tumor cells to cytotoxic CD8+ T cells. For this purpose, we performed RNA sequencing and analyzed the genome-wide gene expression profiles to systematically identify transcriptom reprogramming in the BML-210-treated cells.

2021-10-04 | GSE182954 | GEO

Curtobacterium sp. 260 isolate:DPS 260

Project description:Curtobacterium sp. 260 genome sequencing

| PRJNA709386 | ENA

Effect of depletion of FOXO3A on gene expression of U-937 cells

Project description:To explore the underlying molecular mechanisms of FOXO3A-regulated AML cell function To determine the impact of FOXO3A deficiency on AML cells, we generated knock-out (KO) cells of FOXO3A using small guide RNAs (sgRNAs)

2023-08-01 | GSE218289 | GEO

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