Long non-coding RNA associated with mitogen-activated protein kinase in pancreatic cancer cells.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE216708 | GEO | 2023/01/01
REPOSITORIES: GEO
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Project description:To investigate the long non-coding RNAs associated with mitogen-activated protein kinase in human pancreatic cancer, we isolated total RNA from three pancreatic cancer cell lines (MIAPaCa-2, AsPC-1, PCI-35) with or without 24h treatment of MAP2K inhibitor (U0126). Total transcriptome sequencing analysis was performed in total 6 samples, and then we listed lncRNAs from the raw data.
2023-01-01 | GSE216710 | GEO
Project description:Long non-coding RNAs (lncRNAs) have emerged as a significant player in various cancers, including pancreatic cancer. However, how lncRNAs are aberrantly expressed in cancers is largely unknown. We hypothesized that lncRNAs would be regulated by signaling pathways and contribute to malignant phenotypes of cancer. In this study, to understand the significance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), which is a major aberrant signaling pathway in pancreatic cancer, for the expression of lncRNAs, we performed comparative transcriptome analyses between pancreatic cancer cell lines with or without activation of MAPK. We identified 45 lncRNAs presumably associated with MAPK in pancreatic cancer cells; among these, LINC00941 was consistently upregulated by MAPK. The immediate genomic upstream region flanking LINC00941 was identified as a promoter region, the activity of which was found to be preferentially associated with MAPK activity via ETS-1 binding site. LINC00941 promoted cell proliferation in vitro. Moreover, TCGA data analysis indicated that high expression of LINC00941 was associated with poor prognosis of patients with pancreatic cancer. Transcriptomes comparing transcriptions between cells with and without LINC00941 knockdown revealed 3229 differentially expressed genes involved in 44 biological processes, including the glycoprotein biosynthetic process, beta-catenin-TCF complex assembly, and histone modification. These results indicate that MAPK mediates the aberrant expression of lncRNAs. LINC00941 is the lncRNA by MAPK most consistently promoted, and is implicated in the dismal prognosis of pancreatic cancer. MAPK-associated lncRNAs may play pivotal roles in malignant phenotypes of pancreatic cancer, and as such might represent both potentially valid therapeutic targets and diagnostic biomarkers.
| S-EPMC9818929 | biostudies-literature
Project description:Long non-coding RNAs associated with mitogen-activated protein kinase in pancreatic cancer cells.
| PRJNA895033 | ENA
Project description:Long non-coding RNA associated with mitogen-activated protein kinase in pancreatic cancer cells.
| PRJNA895024 | ENA
Project description:p38 mitogen-activated protein kinases are signaling molecules with major involvement in cancer. A detailed mechanistic understanding of how p38 MAPK family members function is urgently warranted for cancer targeted therapy. The conformational dynamics of the most common member of p38 MAPK family, p38?, are crucial for its function but poorly understood. Here we found that, unlike in other cancer types, p38? is significantly activated in pancreatic adenocarcinoma samples, suggesting its potential for anti-pancreatic cancer therapy. Using a state of the art supercomputer, Anton, long-timescale (39 ?s) unbiased molecular dynamics simulations of p38? show that apo p38? has high structural flexibility in six regions, and reveal potential catalysis mechanism involving a "butterfly" motion. Moreover, in vitro studies show the low-selectivity of the current p38? inhibitors in both human and mouse pancreatic cancer cell lines, while computational solvent mapping identified 17 novel pockets for drug design. Taken together, our study reveals the conformational dynamics and potentially druggable pockets of p38?, which may potentiate p38?-targeting drug development and benefit pancreatic cancer patients.
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Project description:The kinase p38? MAPK (p38?) plays a pivotal role in many biological processes. p38? is activated by canonical upstream kinases that phosphorylate the activation region. The purpose of our study was to determine whether such activation may depend on redox-sensing cysteines within p38?. p38? was activated and formed a disulfide-bound heterodimer with MAP2K3 (MKK3) in rat cardiomyocytes and isolated hearts exposed to H2O2 This disulfide heterodimer was sensitive to reduction by mercaptoethanol and was enhanced by the thioredoxin-reductase inhibitor auranofin. We predicted that Cys-119 or Cys-162 of p38?, close to the known MKK3 docking domain, were relevant for these redox characteristics. The C119S mutation decreased whereas the C162S mutation increased the dimer formation, suggesting that these two Cys residues act as vicinal thiols, consistent with C119S/C162S being incapable of sensing H2O2 Similarly, disulfide heterodimer formation was abolished in H9C2 cells expressing both MKK3 and p38? C119S/C162S and subjected to simulated ischemia and reperfusion. However, the p38? C119S/C162S mutants did not exhibit appreciable alteration in activating dual phosphorylation. In contrast, the anti-inflammatory agent 10-nitro-oleic acid (NO2-OA), a component of the Mediterranean diet, reduced p38? activation and covalently modified Cys-119/Cys-162, probably obstructing MKK3 access. Moreover, NO2-OA reduced the dephosphorylation of p38? by hematopoietic tyrosine phosphatase (HePTP). Furthermore, steric obstruction of Cys-119/Cys-162 by NO2-OA pretreatment in Langendorff-perfused murine hearts prevented the p38-MKK3 disulfide dimer formation and attenuated H2O2-induced contractile dysfunction. Our findings suggest that cysteine residues within p38? act as redox sensors that can dynamically regulate the association between p38 and MKK3.
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Project description:Aldosterone in some tissues increases expression of the mRNA encoding the small monomeric G protein Ki-RasA. Renal A6 epithelial cells were used to determine whether induction of Ki-ras leads to concomitant increases in the total as well as active levels of Ki-RasA and whether this then leads to subsequent activation of its effector mitogen-activated protein kinase (MAPK/extracellular signal-regulated kinase) cascade. The molecular basis and cellular consequences of this action were specifically investigated. We identified the intron 1-exon 1 region (rasI/E1) of the mouse Ki-ras gene as sufficient to reconstitute aldosterone responsiveness to a heterologous promotor. Aldosterone increased reporter gene activity containing rasI/E1 threefold. Aldosterone increased the absolute and GTP-bound levels of Ki-RasA by a similar extent, suggesting that activation resulted from mass action and not effects on GTP binding/hydrolysis rates. Aldosterone significantly increased Ki-RasA and MAPK activity as early as 15 min with activation peaking by 2 h and waning after 4 h. Inhibitors of transcription, translation, and a glucocorticoid receptor antagonist attenuated MAPK signaling. Similarly, rasI/E1-driven luciferase expression was sensitive to glucocorticoid receptor blockade. Overexpression of dominant-negative RasN17, addition of antisense Ki-rasA and inhibition of mitogen-activated protein kinase kinase also attenuated steroid-dependent increases in MAPK signaling. Thus, activation of MAPK by aldosterone is dependent, in part, on a genomic mechanism involving induction of Ki-ras transcription and subsequent activation of its downstream effectors. This genomic mechanism has a distinct time course from activation by traditional mitogens, such as serum, which affect the GTP-binding state and not absolute levels of Ras. The result of such a genomic mechanism is that peak activation of the MAPK cascade by adrenal corticosteroids is delayed but prolonged.
| S-EPMC124141 | biostudies-literature
Project description:We performed a transcriptome analysis to determine what genes were altered in expression when U0126, MAP2K inhibitor, was administered to cells of human pancreatic cancer cell lines. Five genes including ETV5, ETV4, COL13A1, HIST1H4L/H4C13, and WDR62 were found to be particularly downregulated by the inhibition of MAPK pathway, meaning that these genes were preferentially upregulated by the active MAPK. The expression of ETV5 was most modulated, suggesting that ETV5 is strongly associated with the MAPK activity and may play a role in human pancreatic cancer.
2024-06-05 | GSE268817 | GEO
Project description:In plants, mitogen-activated protein kinases (MAPK) have been implicated in signalling associated with many processes, including cellular differentiation, organ development, cell death and stress/hormone signalling. While MAPK cascades are known to act in the cytosol and the nucleus, sequence analysis of the Arabidopsis MAPK cascade proteins predicts the presence of import signals that would target some of them to other organelles. In vitro uptake experiments confirm the predicted import of an oxidant-responsive MAPKK, AtMKK4, into the chloroplast. Unexpectedly, the imported MKK4 protein was not processed through stromal peptidase-dependent cleavage of the N-terminal signal peptide, thus leaving the pre-protein intact. Nevertheless, the N-terminal region was shown to be essential both for the import process and for the ability of MKK4 to activate its cognate MAPK targets in vivo. MKK4 import also occurred irrespective of the activation status of the kinase. The import of this primarily cytosolic oxidant-stimulated AtMKK4 into the chloroplasts, organelles with high redox fluxes, suggests that one of the functions of MKK4 might be to help coordinate intercompartment responses to cellular redox imbalances.
| S-EPMC2633948 | biostudies-literature
Project description:An improved understanding of pathogenic pathways in AKI may identify novel therapeutic approaches. Previously, we conducted unbiased liquid chromatography-tandem mass spectrometry-based protein expression profiling of the renal proteome in mice with acute folate nephropathy. Here, analysis of the dataset identified enrichment of pathways involving NFκB in the kidney cortex, and a targeted data mining approach identified components of the noncanonical NFκB pathway, including the upstream kinase mitogen-activated protein kinase kinase kinase 14 (MAP3K14), the NFκB DNA binding heterodimer RelB/NFκB2, and proteins involved in NFκB2 p100 ubiquitination and proteasomal processing to p52, as upregulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in acute folate nephropathy and human AKI. In vivo, kidney expression levels of NFκB2 p100 and p52 increased rapidly after folic acid injection, as did DNA binding of RelB and NFκB2, detected in nuclei isolated from the kidneys. Compared with wild-type mice, MAP3K14 activity-deficient aly/aly (MAP3K14aly/aly) mice had less kidney dysfunction, inflammation, and apoptosis in acute folate nephropathy and less kidney dysfunction and a lower mortality rate in cisplatin-induced AKI. The exchange of bone marrow between wild-type and MAP3K14aly/aly mice did not affect the survival rate of either group after folic acid injection. In cultured tubular cells, MAP3K14 small interfering RNA targeting decreased inflammation and cell death. Additionally, cell culture and in vivo studies identified the chemokines MCP-1, RANTES, and CXCL10 as MAP3K14 targets in tubular cells. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target.
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