Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
|
| pubmed:dateCreated |
1996-8-2
|
| pubmed:abstractText |
Tumor necrosis factor-alpha (TNF-alpha) is a proposed mediator of insulin resistance in obese/diabetic animals through its effects on tyrosine phosphorylation of the insulin receptor and its substrate, insulin receptor substrate-1. In this study, the acute effects of TNF-alpha on the mitogen-activated protein kinase (MAPK) signalling cascade were examined in cultured rat skeletal muscle cell line, L6. Insulin treatment of L6 cells resulted in a rapid increase in MAPK activity (> twofold in 5 min with 10 nM insulin). Prior treatment with TNF-alpha for 60 min blocked subsequent insulin-induced activation of MAPK in a dose- and time-dependent manner. Metabolic labelling studies with inorganic [32P]phosphate followed by immuno-precipitation of MAPK and its upstream activator, mitogen-activated protein kinase kinase, indicated decreased phosphorylation of MAPK and its kinase in response to insulin in cells exposed to TNF-alpha. This effect of TNF-alpha was not due to inhibition of insulin-stimulated p21ras-GTP loading or Raf-1 phosphorylation. Low concentrations (2 nM) of okadaic acid, a serine/threonine phosphatase inhibitor, prevented TNF-alpha-induced inhibition of MAPK and restored insulin's effect on MAPK activity, while orthovanadate (a tyrosine phosphatase inhibitor), inhibitor 2 (phosphatase-1 inhibitor) and FK506 (phosphatase-2B inhibitor) were ineffective. These results suggested an involvement of an okadaic-acid-sensitive serine/threonine phosphatase in TNF-alpha-induced blockade of insulin's effect on MAPK and/or its kinase. Therefore, we examined the effect of TNF-alpha on protein phosphatase-1 (PP-1) and protein phosphatase-2A (PP-2A) activities. As reported by us earlier, insulin rapidly stimulated PP-1 and concomitantly inhibited PP-2A activities in control cells. TNF-alpha treatment blocked insulin-induced activation of PP-1. In contrast to PP-1, TNF-alpha caused a 60% increase in PP-2A activity and insulin failed to prevent this TNF-alpha effect. The time course of PP-2A activation by TNF-alpha preceded the kinetics of inhibition of MAPK. Cell-permeable ceramide analogs mimicked the TNF-alpha effect on MAPK inhibition and PP-2A activation. We conclude that TNF-alpha abrogates the insulin effect on MAPK activation by increasing dephosphorylation of MAPK kinase via an activated phosphatase.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Ceramides,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 10,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoprotein Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Phosphatase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Phosphatase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-raf,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins p21(ras),
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
May
|
| pubmed:issn |
0014-2956
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
15
|
| pubmed:volume |
238
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
214-20
|
| pubmed:dateRevised |
2011-11-17
|
| pubmed:meshHeading |
pubmed-meshheading:8665940-Animals,
pubmed-meshheading:8665940-Cell Membrane Permeability,
pubmed-meshheading:8665940-Cells, Cultured,
pubmed-meshheading:8665940-Ceramides,
pubmed-meshheading:8665940-Enzyme Inhibitors,
pubmed-meshheading:8665940-Insulin,
pubmed-meshheading:8665940-Mitogen-Activated Protein Kinase 10,
pubmed-meshheading:8665940-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:8665940-Mitogen-Activated Protein Kinases,
pubmed-meshheading:8665940-Muscle, Skeletal,
pubmed-meshheading:8665940-Phosphoprotein Phosphatases,
pubmed-meshheading:8665940-Phosphorylation,
pubmed-meshheading:8665940-Protein Kinases,
pubmed-meshheading:8665940-Protein Phosphatase 1,
pubmed-meshheading:8665940-Protein Phosphatase 2,
pubmed-meshheading:8665940-Protein-Serine-Threonine Kinases,
pubmed-meshheading:8665940-Protein-Tyrosine Kinases,
pubmed-meshheading:8665940-Proto-Oncogene Proteins,
pubmed-meshheading:8665940-Proto-Oncogene Proteins c-raf,
pubmed-meshheading:8665940-Proto-Oncogene Proteins p21(ras),
pubmed-meshheading:8665940-Rats,
pubmed-meshheading:8665940-Signal Transduction,
pubmed-meshheading:8665940-Tumor Necrosis Factor-alpha
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
Effect of tumor necrosis factor-alpha on insulin-stimulated mitogen-activated protein kinase cascade in cultured rat skeletal muscle cells.
|
| pubmed:affiliation |
Diabetes Research Laboratory, Winthrop University Hospital, Mineola, NY 11501, USA.
|
| pubmed:publicationType |
Journal Article
|