The Stat3 target Mettl8 regulates mouse ESCs differentiation via inhibiting JNK pathway
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE112360
PROVIDER: PRJNA445796 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6902181_1.fastq.gz | Fastqsanger.gz | |||
| SRR6902181_2.fastq.gz | Fastqsanger.gz | |||
| SRR6902182_1.fastq.gz | Fastqsanger.gz | |||
| SRR6902182_2.fastq.gz | Fastqsanger.gz |
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Project description:The capacity of embryonic stem cells to differentiate into all lineages of mature organism is precisely regulated by cellular signaling factors. STAT3 is a crucial transcription factor that plays a central role in maintaining embryonic stem cells identity. However the underlying mechanism how Stat3 directs differentiation is still not completely understood. Here we show that Stat3 positively regulates gene expression of methyltransferase like protein 8 (Mettl8) in mouse ES cells. We found that Mettl8 is dispensable for pluripotency but affects ESCs differentiation. Subsequently we discovered that Mettl8 interacts with Mapkbp1’s mRNA, which is an intermediate factor in JNK signaling, and inhibits the translation of the mRNA. Thereby, Mettl8 prohibits the activation of JNK signaling and enhances the differentiation of mouse ESCs. Collectively, our study uncovers a Stat3 target Mettl8 which regulates mouse ESCs differentiation via JNK signaling.
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Project description:The capacity of embryonic stem cells (ESCs) to differentiate into all lineages of mature organism is precisely regulated by cellular signaling factors. STAT3 is a crucial transcription factor that plays a central role in maintaining ESC identity. However, the underlying mechanism by which STAT3 directs differentiation is still not completely understood. Here, we show that STAT3 positively regulates gene expression of methyltransferase-like protein 8 (Mettl8) in mouse ESCs. We found that METTL8 is dispensable for pluripotency but affects ESC differentiation. Subsequently, we discovered that METTL8 interacts with Mapkbp1's mRNA, which is an intermediate factor in c-Jun N-terminal kinase (JNK) signaling, and inhibits the translation of the mRNA. Thereby, METTL8 prohibits the activation of JNK signaling and enhances the differentiation of mouse ESCs. Collectively, our study uncovers a STAT3 target, Mettl8, which regulates mouse ESC differentiation via JNK signaling.
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Project description:The incidence for bladder urothelial carcinoma (UC), a common malignancy of the urinary tract, is about three times higher in men than in women. High expression of the mitotic kinase BUB1 is associated with a subset of human cancers, but how BUB1 drive Bladder tumorigenesis mechanism was unknown. Using a microarray approach, we identified BUB1 higher expression in BC. Moreover we found BUB1, a member of the kinase family as a STAT3 interactor and phosphorylated STAT3 at Ser727 in cell of bladder cancer. In vitro binding and kinase assays showed that BUB1 directly band STAT3 and phosphorylated STAT3. Furthermore, the BUB1/STAT3 complex promoted STAT3 target gene transcription. Depletion of BUB1 and expression of BUB1 kinase mutants abrogated target gene transcription, highlighting the essential function of the kinase activity in STAT3 target gene activation. Pharmacological inhibitors of BUB1 (2OH-BNPP1) was able to inhibit the growth of Bladder cancer cell xenograft. This kinase may present an attractive candidate for drug targeting in Bladder cancer.
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Project description:Target BUB1 kinase as a therapeutic strategy for inhibiting STAT3 signal pathway in Bladder cancer
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Project description:Although the oncogenic signalings driven by amplification and mutations of EGF receptor (EGFR) gene play a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59), acting as a new downstream effector of EGFR signaling, regulates STAT3 activation in glioblastoma. EGFR signaling leads to TRIM59 upregulation through SOX9 that results in enhancing TRIM59 interaction with STAT3 in nucleus, and inhibiting STAT3 association with TC45 (the nuclear form of T cell protein tyrosine phosphatase TC-PTP), thereby maintaining STAT3 phosphorylation and activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumorigenesis of GBM cells. Moreover, evaluation of GBM patient samples reveals an association among EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR-STAT3 signaling and a potential therapeutic target for GBM patients with EGFR activation.
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Project description:The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here we show that culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 6-fold increase in number. These expanded CD34+ cells repopulated recipient mice for 20 weeks and can form secondary engraftment that lasted for more than 21 weeks. Knockdown of c-Jun, a major downstream target in the JNK pathway, significantly promoted the expansion of hematopoietic stem and progenitor cells (HSPCs). Our findings demonstrate a critical role of JNK pathway in regulating HSC expansion, provide new insights into HSC self-renewal mechanism, and may lead to improved clinical application of HSCs.
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