Search results for "MAP kinase"
showing 10 items of 178 documents
Evolution of osmosensing signal transduction in Metazoa: stress-activated protein kinases p38 and JNK.
2001
Sponges (Porifera) represent the most basal branch of the Metazoa alive today. We show that two central stress-activated protein kinases involved in the osmosensing pathway, p38 mitogen-activated protein kinase (MAPK) and JNK, can complement for the ancestral MAPK Hog1 in the yeast Saccharomyces cerevisiae. S. cerevisiae mutants lacking Hog1 (hog1-Delta 1) have been complemented with the sponge SDJNK and SDp38 genes. Western blotting has revealed that, after transformation, the hog1-Delta 1+ SDJNK(sense) and hog1-Delta 1+ SDp38(sense) clones express the sponge proteins. Functional studies have demonstrated that the complemented clones grow under hyperosmotic conditions (0.6 M NaCl). Further…
Colony-stimulating factor-1-induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing dif…
2009
Abstract The differentiation of human peripheral blood monocytes into resident macrophages is driven by colony-stimulating factor-1 (CSF-1), which upon interaction with CSF-1 receptor (CSF-1R) induces within minutes the phosphorylation of its cytoplasmic tyrosine residues and the activation of multiple signaling complexes. Caspase-8 and -3 are activated at day 2 to 3 and contribute to macrophage differentiation, for example, through cleavage of nucleophosmin. Here, we show that the phosphatidylinositol-3 kinase and the downstream serine/threonine kinase AKT connect CSF-1R activation to caspase-8 cleavage. Most importantly, we demonstrate that successive waves of AKT activation with increasi…
Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: A compa…
2017
As the knowledge on the estrogenic system in the brain grows, the possibilities to modulate it in order to afford further neuroprotection in brain damaging disorders so do it. We have previously demonstrated the ability of the selective estrogen receptor modulator, bazedoxifene (BZA), to reduce experimental ischemic brain damage. The present study has been designed to gain insight into the molecular mechanisms involved in such a neuroprotective action by investigating: 1) stroke-induced apoptotic cell death; 2) expression of estrogen receptors (ER) ERα, ERβ and the G-protein coupled estrogen receptor (GPER); and 3) modulation of MAPK/ ERK1/2 and PI3K/Akt signaling pathways. For comparison, …
A Phase Ib Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treat…
2017
Abstract Lessons Learned Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents. The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested. Background KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibitio…
Mir-4674 Regulates Angiogenesis In Tissue Injury By Targeting P38K Signaling In Endothelial Cells
2020
Neoangiogenesis is critical for tissue repair in response to injury such as myocardial ischemia or dermal wound healing. MicroRNAs are small noncoding RNAs and important regulators of angiogenesis under physiological and pathological disease states. Therefore, identification of microRNAs that may restore impaired angiogenesis in response to tissue injury may provide new targets for therapy. Using a microRNA microarray profiling approach, we identified a human-specific microRNA, miR-4674, that was significantly decreased in patients after myocardial tissue injury and had an endothelial cell (EC)-enriched expression pattern. Functionally, overexpression of miR-4674 markedly attenuated EC pro…
High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1β in osteoarthritic synoviocytes
2010
Introduction High mobility group box 1 (HMGB1) is released by necrotic cells or secreted in response to inflammatory stimuli. Extracellular HMGB1 may act as a pro-inflammatory cytokine in rheumatoid arthritis. We have recently reported that HMGB1 is released by osteoarthritic synoviocytes after activation with interleukin-1beta (IL-1β) The present study investigated the role of HMGB1 in synovial inflammation in osteoarthritis (OA). Methods HMGB1 was determined in human synovium using immunohistochemistry, comparing normal to OA. OA synoviocytes were incubated with HMGB1 at 15 or 25 ng/ml in the absence or presence of IL-1β (10 ng/ml). Gene expression was analyzed by quantitative PCR and pro…
Studies on protein kinases involved in regulation of nucleocytoplasmic mRNA transport
1988
The rate of energy-dependent nucleoside triphosphatase (NTPase)-mediated nucleocytoplasmic translocation of poly(A)-containing mRNA [poly(A)+mRNA] across the nuclear envelope is thought to be regulated by poly(A)-sensitive phosphorylation and dephosphorylation of nuclear-envelope protein. Studying the phosphorylation-related inhibition of the NTPase, we found that phosphorylation of one polypeptide of rat liver envelopes by endogenous NI- and NII-like protein kinase was particularly sensitive to poly(A). This polypeptide (106 kDa) was also phosphorylated by nuclear-envelope-bound Ca2+-activated and phospholipid-dependent protein kinase (protein kinase C). Activation of kinase C by tumour-pr…
Significant in vivo anti-inflammatory activity of Pytren4Q-Mn a superoxide dismutase 2 (SOD2) mimetic scorpiand-like Mn (II) complex.
2015
Background The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight. Background/Methodology We have recently reported that two SOD mimetic compounds, the MnII complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q MnII complexes, in cultured macrophages …
Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mtor pathways in controlling growth and sensitivity to therapy-implications for cancer and aging
2011
Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described …
Pentoxifylline Prevents Loss of PP2A Phosphatase Activity and Recruitment of Histone Acetyltransferases to Proinflammatory Genes in Acute Pancreatitis
2009
Mitogen-activated protein kinases (MAPKs) are considered major signal transducers early during the development of acute pancreatitis. Pentoxifylline is a phosphodiesterase inhibitor with marked anti-inflammatory properties through blockade of extracellular signal regulated kinase (ERK) phosphorylation and tumor necrosis factor alpha production. Our aim was to elucidate the mechanism of action of pentoxifylline as an anti-inflammatory agent in acute pancreatitis. Necrotizing pancreatitis induced by taurocholate in rats and taurocholate-treated AR42J acinar cells were studied. Phosphorylation of ERK and ERK kinase (MEK1/2), as well as PP2A, PP2B, and PP2C serine/threonine phosphatase activiti…