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The Role of MAP Kinases, Phosphatidylinositol 3-Kinase, and Ceramide in LPS-induced Signaling in Macrophages
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Anthony L. DeFranco, Alexander J. Finn, Julie Hambleton, Mary T. Crowley, Mary Lee MacKichan, Steven L. Weinstein
Although these three signaling pathways are incompletely understood, a consensus view of the nature of these pathways is shown in Figure 1. Typically, the Erk pathway is activated by Ras and is important for activating transcription from serum-response elements by phosphorylating the Ets family ternary complex factors such as Elk-1. The JNK and p38 pathways may be downstream of another subgroup of low molecular weight GTP-binding proteins, which includes the Rac and CDC42 proteins. JNK and p38 MAP kinase pathways are often activated in cells subjected to stressful conditions such as osmotic shock and hence have also been called stress-activated protein kinases (SAPKs). A major target for JNK is, as the name implies, the bZIP family transcription factor c-Jun. Phosphorylation by JNK of serines 63 and 73 within c-Jun greatly increases its ability to stimulate transcription without affecting its binding to DNA. This promotes gene transcription at AP-1 sites, as can be observed with a reporter gene assay in macrophages stimulated by LPS (22). The p38 MAP kinase can also promote the activity of transcription factors, notably the myocyte enhancer factor MEF2C (31), which may regulate the c-jun promoter. In addition to their ability to act directly on transcription factors, MAP kinases can act on other protein kinases to activate them. For example, in many cell types, Erkl and Erk2 activate p90RSK (27) and p38 activates MAPKAP kinase-2 (32).
Proto-Oncogene and Onco-Suppressor Gene Expression
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The Ets-related protein Elk-1 is expressed in adult lung and testis as well as in lymphoid and myeloid cells. Elk-1 forms a ternary complex with the SRF and SRE, suggesting that Elk-1 could be homologous to the p62 c-Fos regulatory factor.268 Elk-1, like the c-Ets-1 protein, binds in a sequence-specific manner to the PEA-3 DNA motif.
Tumor Suppressor Genes and Oncogenes
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Ras helps to link activated tyrosine kinase receptors to downstream events by acting as a molecular switch. It is in the “off’’ position when bound to GDP and in the “on’’ position when bound to GTP. Some tyrosine kinase receptors phosphorylate themselves on tyrosine residues, which then bind to other proteins that have SH2 domains that dock to phosphorylated tyrosine residues. These proteins with SH2 domains then link to other proteins (such as Sos) that activate ras. Activated ras initiates a serine/threonine phosphorylation cascade, which eventually activates a kinase called mitogen-activated protein kinase (MAP kinase). Eventually, such activation stimulates the action of a number of transcription factors, including jun and elk-1 (Fig. 3). Figure 3 shows another important point: namely, that protein kinase C can also activate MAP kinase.
Sirtuins as therapeutic targets for improving delayed wound healing in diabetes
Published in Journal of Drug Targeting, 2022
Fathima Beegum, Anuranjana P. V., Krupa Thankam George, Divya K. P., Farmiza Begum, Nandakumar Krishnadas, Rekha R. Shenoy
The role of SIRT 1 in other diabetic complications was also emphasised. Resveratrol was found to be effective in diabetic foot syndrome through SIRT 1 activation and tissue regeneration [105]. It increased the endothelial cell proliferation by activating the ERK signalling pathway and improved cutaneous wound healing [105]. Extracellular signal regulated kinase (ERK) signalling pathway is one of the major signalling cascades of mitogen activated protein kinase signalling pathway. The activation of ERK by SIRT 1 phosphorylates ribosomal S6 kinase (RSK) and ERK translocates to the nucleus where they activate transcription factors including CREB, Fos proto-oncogene (FOS), ETS domain containing protein (Elk-1) eventually resulting in effector protein synthesis causing changes in cell proliferation and survival. CREB, being a cellular transcription factor can enhance gene transcription for above ten times. c-Fos, 380 amino acid protein with basic leucine zipper region for dimerisation and DNA binding and a transactivation domain at C-terminus, is involved in cell proliferation, differentiation and survival. Elk-1 is a protein that is encoded in humans by ELK-1 gene, function as transcription activator. As a result of the activation of SIRT-1, there is enhanced cellular proliferation and improved cutaneous wound healing. The polymer-based sponge loaded with chitosan sodium hyaluronate-resveratrol stimulates tissue regeneration and formation of granulation tissue to facilitate healing of wounds [106].
Analysis of the protective effects of γ-aminobutyric acid during fluoride-induced hypothyroidism in male Kunming mice
Published in Pharmaceutical Biology, 2019
Haoyue Yang, Ronge Xing, Song Liu, Huahua Yu, Pengcheng Li
The involvement of apoptosis in fluorosis is an emerging research topic, and sustained ERK1/2 signaling is intricately linked to apoptosis induction (Chattopadhyay et al. 2011). When normal and malignant cells are stimulated by the external environment, ERK1/2 signaling is activated by phosphorylation, which leads to the translocation of ERK1/2 from the cytoplasm to the nucleus. Activated ERK1/2 induces the transcription of Elk-1, activator protein-1, nuclear factor kappa beta, c-fos and c-jun, which participate in cell differentiation and apoptosis (Goetze et al. 2001; Tresini et al. 2001). In this study, after exposing mice to NaF, ERK1/2 expression increased significantly, suggesting that fluoride mediates apoptosis in thyroid follicular epithelial cells through the sustained activation of ERK1/2. The daily administration of 50 mg/kg GABA over 14 days significantly inhibited ERK1/2, demonstrating that GABA mitigates fluoride-induced apoptosis by inhibiting the activation of ERK1/2. The highly hydrophobic 18-kDa TSPO, located in the mitochondrial outer membrane, is rich in tryptophan and a key factor in mitochondrial apoptosis (Kita et al. 2004; Kita and Furukawa 2008; Nothdurfter et al. 2012; Banati et al. 2014). Indeed, upon stimulation by various chemicals, TSPO becomes upregulated, thus generating mitochondrial reactive oxygen species, activating voltage-dependent anion channels, releasing cytochrome C and activating caspase-9 and caspase-3, which leads to apoptosis (Casellas et al. 2002). Our results showed that the upregulation of TSPO expression induced by NaF was mitigated by treatment with GABA, which blocked mitochondrial apoptosis, thus protecting thyroid follicular epithelial cells.
Myosin light chain kinase regulates intestinal permeability of mucosal homeostasis in Crohn’s disease
Published in Expert Review of Clinical Immunology, 2020
Both mouse and cell models have indicated that the TNF-α induces increased TJ permeability by activating (MAPK) ERK1/2 pathway, rather than the p38 kinase pathway. The activation of the ERK1/2 pathway by TNF-α leads to the phosphorylation of the transcription factor Elk-1, which contains the ETS domain. Activated Elk-1 translocates into the nucleus, binds to its cis-binding motif on the MLCK promoter region, and activates the gene transcription of MLCK [103]. Additionally, the TNF-α blocker can significantly reduce the expression of MLCK, further indicating that TNF-α can lead to the expression of MLCK [104].