Phosphodiesterase 12 facilitates the growth and metastatic capabilities of gastric cancer cells by activating the TCAF2/JAK2/STAT3 axis
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ABSTRACT:
PROVIDER: PRJNA1245444 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32958970_1.fastq.gz | Fastqsanger.gz | |||
| SRR32958970_2.fastq.gz | Fastqsanger.gz | |||
| SRR32958971_1.fastq.gz | Fastqsanger.gz | |||
| SRR32958971_2.fastq.gz | Fastqsanger.gz | |||
| SRR32958972_1.fastq.gz | Fastqsanger.gz |
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Project description:Pressure ulcers (PU) is a complex and serious clinical problem. Deep tissue injury is either the outcome or the trigger of deep PU. However, the cellular and molecular mechanisms that contribute to the pathogenesis of deep PU remain unclear. In this study, the degeneration characteristics, increased autophagy and apoptosis were observed in deep PU muscle tissues by H&E staining, transmission electron microscope, TUNEL staining and western blot analysis. We further conducted quantitative liquid chromatography-tandem mass spectrometry analysis to explore the proteome of deep PU muscle, a total of 520 proteins were differently expressed, including 427 up-regulated and 93 down-regulated. In particular, downregulation was observed for Janus Kinase 2 (JAK2). Intriguingly, we showed that a distinctly reduced expression of JAK2 in C2C12 myoblasts exposed to oxygen-glucose deprivation and reoxygenation insult. Ex vivo, JAK2 overexpressed myoblasts exhibited decrease of autophagy and apoptosis with the same treatment, along with less cell death. Finally, western blot analysis determined that p-JAK2, p-PI3K, p-AKT, p-mTOR and p-ERK1/2 were significantly elevated, accompanied by JAK2 overexpression, but without p-STAT3. In conclusion, these results demonstrated that both autophagy and apoptosis involve in muscle damage of deep PU, and JAK2 may play an important protective role in muscular ischemia and reperfusion injury by activating AKT and ERK1/2 pathway to inhibit autophagy and apoptosis.
2019-11-12 | PXD009512 | Pride
Project description:SPAG9-JAK2 is a novel fusion gene identified in a pediatric patient with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). In this study, we performed functional analysis of the SPAG9-JAK2 fusion to establish molecular targeted therapy. Ba/F3 cells expressing SPAG9-JAK2 generated by retroviral transduction (Ba/F3-SPAG9-JAK2), proliferated in the absence of IL-3, and exhibited constitutive phosphorylation of the tyrosine residues in the JAK2 kinase domain of the fusion protein and STAT3/STAT5. Mutation of tyrosine residues in the JAK2 kinase domain (SPAG9-JAK2 mut) abolished IL-3 independence, but had no influence on STAT3/STAT5 phosphorylation levels. Gene expression analysis revealed that Stat1 was significantly up-regulated in Ba/F3-SPAG9-JAK2 cells. STAT1 was also phosphorylated in Ba/F3-SPAG9-JAK2 but not SPAG9-JAK2 mut cells, suggesting that STAT1 is key for SPAG9-JAK2-mediated cell proliferation. Consistently, STAT1 induced expression of the anti-apoptotic proteins, BCL-2 and MCL-1, as did SPAG9-JAK2, but not SPAG9-JAK2 mut. Ruxolitinib abrogated Ba/F3-SPAG9-JAK2-mediated proliferation in vitro, but was insufficient in vivo. Venetoclax (a BCL-2 inhibitor) or AZD5991 (an MCL-1 inhibitor) enhanced the effects of ruxolitinib on Ba/F3-SPAG9-JAK2 in vitro. These findings suggest that activation of the JAK2-STAT1-BCL-2/MCL-1 axis contributes to SPAG9-JAK2-related aberrant growth promotion. BCL-2 or MCL-1 inhibition is a potential therapeutic option for B-ALL with SPAG9-JAK2 fusion.
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Project description:Purpose: Although the B-cell receptor (BCR) signal plays a critical role in CLL cell survival and a target of current therapies (ibrutinib targets Bruton’s tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the “CLL cell-survival signaling network” is largely undefined. Experimental Design: CLL patients were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism. Results: We detected that compared to normal B-cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its non-canonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR-signal in CLL cells via LYN/BTK axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR-inhibitors or venetoclax (a BCL2-inhibitor) induced apoptosis synergistically in CLL cells. Conclusions: These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some CLL patients.
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Project description:During the occurrence of sepsis, the liver plays a crucial role in immune defense. However, the excessive immune response within the liver can also make it the main target organ for sepsis-related injuries. In this paper, our aim is to explore the protective role of RP105 in liver injury caused by sepsis and clarify its underlying molecular mechanisms. We established a cecal ligation and puncture (CLP) model using RP105 knockout mice. We observed the protective effect of RP105 on liver damage caused by sepsis. We also conducted RNA sequencing (RNA-Seq) analysis on the CLP group and the RP105 knockout CLP group. Furthermore, through in vitro and in vivo experiments, we found that RP105 alleviated liver injury caused by sepsis through the classical regulation of SOCS2 via the JAK2/STAT3 signaling pathway.
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Project description:Renal fibrosis is an important pathological change in the development of progressive kidney diseases. Ubiquitination is a post-translational modification of proteins involved in the regulation of various pathophysiological processes. In this study, we found that the deubiquitinating enzyme YOD1 is significantly upregulated in the kidney tissues of Ang II-challenged mice and Ang II upregulates YOD1 expression in renal tubular epithelial cells. YOD1 deficiency significantly alleviated renal injury and fibrosis induced by Ang II infusion in mice. Mechanistically, RNA-seq and co-immunoprecipitation analysis showed a pro-fibrotic protein, JAK2, as a YOD1-binding protein. We identify that JAK2 interacts with the C-terminal Znf domain of YOD1. YOD1 removed K48-linked ubiquitination of JAK2 at residue K970 via its active site C155, which stabilizes JAK2 and then maintains JAK2/STAT3 signaling pathway activation to induce pro-fibrotic gene expression in renal tubular epithelial cells. JAK2 inhibitors reversed the renal fibrosis promoted by YOD1 in mice. We also show increased levels of YOD1 and JAK2 in the kidney tissues of patients with renal fibrosis. In addition, YOD1 knockout significantly prevents unilateral ureteral ligation (UUO)-induced renal fibrosis in mice. Collectively, these findings identify YOD1 as a novel regulator in renal fibrosis via deubiquitinating JAK2.
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