p38 MAPK Is Involved in Activin A- and Hepatocyte Growth Factor-mediated Expression of Pro-endocrine Gene Neurogenin 3 in AR42J-B13 Cells

Ogihara, Takeshi; Watada, Hirotaka; Kanno, Rei; Ikeda, Fuki; Nomiyama, Takashi; Tanaka, Yasushi; Nakao, Akihiro; German, Michael S.; Kojima, Itaru; Kawamori, Ryuzo

doi:10.1074/jbc.m302684200

Cited by 42 publications

(32 citation statements)

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“…For instance, DN MKK3 rather than DN MKK6 blocks ␣ v integrin-mediated p38 activation in invasive breast cancer cells (25). Similarly, activin A and hepatocyte growth factor-mediated p38 activation is inhibited by DN MKK3, but not by DN MKK6 in pancreatic cancer cells (26). Hypoxia-induced endoglin expression in mouse endothelial cell line is also inhibited by DN MKK3 (27).…”

Section: Discussionmentioning

confidence: 78%

Regulation of p38 MAPK by MAPK Kinases 3 and 6 in Fibroblast-Like Synoviocytes

Hammaker

Boyle

Firestein

2005

The Journal of Immunology

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The p38 MAPK signal transduction pathway is a key regulator of IL-1 and TNF-α production in rheumatoid arthritis. Previous studies demonstrated that upstream MAPK kinases (MKK3 and MKK6) that regulate p38 are activated in rheumatoid arthritis synovium. However, their functional relevance in fibroblast-like synoviocytes (FLS) has not been determined. To investigate the relative contribution of MKK3 and MKK6 to p38 activation, the effect of dominant-negative (DN) MKK3 and MKK6 constructs on cultured FLS was evaluated. Cultured FLS were stimulated with medium or IL-1β, and immunoblotting was performed. In some experiments, cells were lysed and immunoprecipitated with anti-p38 Ab, followed by in vitro kinase assay with [γ-32P]ATP and GST-activating transcription factor-2 as substrate. IL-1β rapidly induced p38 phosphorylation in cells transfected with empty vector (pcDNA3.1), but was inhibited by 25% in cells expressing DN MKK3 or DN MKK6. Cotransfection with both DN plasmids decreased phospho-p38 by almost 75%. In vitro kinase assays on IL-1-stimulated FLS also showed that the combination of DN MKK3 and DN MKK6 markedly decreased kinase activity compared with empty vector or the individual DN plasmids. Furthermore, IL-1β-induced IL-8, IL-6, and matrix metalloproteinase-3 protein production was significantly inhibited in DN MKK3/DN MKK6-transfected cells. The constructs had no effect on the respective mediator mRNA levels. These data demonstrate that MKK3 and MKK6 make individual contributions to p38 activation in FLS after cytokine stimulation, but that both must be blocked for maximum inhibition.

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Section: Discussionmentioning

confidence: 78%

Regulation of p38 MAPK by MAPK Kinases 3 and 6 in Fibroblast-Like Synoviocytes

Hammaker

Boyle

Firestein

2005

The Journal of Immunology

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“…Thus, endocrine differentiation of the amphicrine AR4-2J cell line is induced by addition of activin, together with betacellulin or HGF, and this effect was recently shown to operate directly by means of elements in the Ngn3 promoter (Ogihara et al, 2003). Similarly, culturing pancreatic explants with the TGF␤ activin-antagonist follistatin leads to a decline in endocrine development, whereas exocrine development is increased (Miralles et al, 1998).…”

Section: Establishing a Pro-endocrine Field During Notch Signalingmentioning

confidence: 99%

Gene regulatory factors in pancreatic development

Jensen

2003

Developmental Dynamics

348

289

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The intensity of research on pancreatic development has increased markedly in the past 5 years, primarily for two reasons: we now know that the insulin-producing ␤-cells normally arise from an endodermally derived, pancreasspecified precursor cell, and successful transplants of islet cells have been performed, relieving patients with type I diabetes of symptoms for extended periods after transplantation. Combining in vitro ␤-cell formation from a pancreatic biopsy of a diabetic patient or from other stem-cell sources followed by endocrine cell transplantation may be the most beneficial route for a future diabetes therapy. However, to achieve this, a thorough understanding of the genetic components regulating the development of ␤-cells is required. The following review discusses our current understanding of the transcription factor networks necessary for pancreatic development and how several genetic interactions coming into play at the earliest stages of endodermal development gradually help to build the pancreatic organ.

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“…The samples were sonicated on ice and centrifuged at 15,000g at 4°C for 30 min. The supernatants were collected and Western blotting analysis was performed as previously described (13). For the immunoprecipitation assay, the isolated tissues were homogenized in radioimmunoprotein assay buffer and immunoprecipitation was conducted by incubating supernatant containing the same amount of protein with the indicated antibody and protein G sepharose for 1 hour at 4°C (12).…”

Section: Conclusion-ourmentioning

confidence: 99%

Impact of Oxidative Stress and Peroxisome Proliferator–Activated Receptor γ Coactivator-1α in Hepatic Insulin Resistance

et al. 2008

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OBJECTIVE-Recent studies identified accumulation of reactive oxygen species (ROS) as a common pathway causing insulin resistance. However, whether and how the reduction of ROS levels improves insulin resistance remains to be elucidated. The present study was designed to define this mechanism.RESEARCH DESIGN AND METHODS-We investigated the effect of overexpression of superoxide dismutase (SOD)1 in liver of obese diabetic model (db/db) mice by adenoviral injection.RESULTS-db/db mice had high ROS levels in liver. Overexpression of SOD1 in liver of db/db mice reduced hepatic ROS and blood glucose level. These changes were accompanied by improvement in insulin resistance and reduction of hepatic gene expression of phosphoenol-pyruvate carboxykinase and peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣), which is the main regulator of gluconeogenic genes. The inhibition of hepatic insulin resistance was accompanied by attenuation of phosphorylation of cAMP-responsive element-binding protein (CREB), which is a main regulator of PGC-1␣ expression, and attenuation of Jun NH 2 -terminal kinase (JNK) phosphorylation. Simultaneously, overexpression of SOD1 in db/db mice enhanced the inactivation of forkhead box class O1, another regulator of PGC-1␣ expression, without the changes of insulin-induced Akt phosphorylation in liver. In hepatocyte cell lines, ROS induced phosphorylation of JNK and CREB, and the latter, together with PGC-1␣ expression, was inhibited by a JNK inhibitor. A ccumulation of reactive oxygen species (ROS) plays a critical role in the pathogenesis of various diseases. ROS are generated by the electron transport chain in mitochondrial respiration and are thus increased in conditions associated with enhanced oxidation of energy substrate such as glucose and free fatty acids. Furthermore, ROS is produced by NADPH oxidase, which is activated by various cytokines. The state of insulin resistance is accompanied by increases in the levels of blood glucose, free fatty acids, and adipocytokines and is thus regarded as a state of increased exposure to ROS (1,2). Although the exact mechanism of insulin resistance is not fully understood, recent data implicate ROS in the pathogenesis of multiple forms of insulin resistance (3-5). However, there is little or no information on how ROS induce insulin resistance in vivo. CONCLUSIONS-OurThe tissue ROS level in each organ depends on the production and elimination of ROS. Superoxide dismutases (SODs) are major antioxidant enzymes that degrade superoxide into hydrogen peroxide. At present, three distinct isoforms of SOD have been identified in mammals (6). SOD1, or CuZn-SOD, is a copper-and zinc-containing homodimer. Although this enzyme had been regarded to be expressed exclusively in the cytoplasm, at least in rodent liver, it is found both in the intermembrane space of mitochondria and in the cytosol (7). SOD2, or Mn-SOD, is a manganese-containing enzyme found almost exclusively in the mitochondria. SOD3, or EC-SOD, is the most recently characterized SOD...

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p38 MAPK Is Involved in Activin A- and Hepatocyte Growth Factor-mediated Expression of Pro-endocrine Gene Neurogenin 3 in AR42J-B13 Cells

Abstract: Neurogenin3 (ngn3) is a transcription factor that is

Cited by 42 publications

References 43 publications

Regulation of p38 MAPK by MAPK Kinases 3 and 6 in Fibroblast-Like Synoviocytes

Regulation of p38 MAPK by MAPK Kinases 3 and 6 in Fibroblast-Like Synoviocytes

Gene regulatory factors in pancreatic development

Impact of Oxidative Stress and Peroxisome Proliferator–Activated Receptor γ Coactivator-1α in Hepatic Insulin Resistance

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