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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
|
| pubmed:dateCreated |
1996-6-5
|
| pubmed:abstractText |
The murine fibrosarcoma cell line WEHI 164 is well known for its susceptibility to tumor necrosis factor (TNFalpha). We have studied the activation of the transcription factor NF-kappaB when WEHI 164 cells are challenged with TNFalpha. NF-kappaB is retained in the cytoplasm of unchallenged cells by its inhibitor IkappaB-alpha. Upon cellular stimulation, IkappaB-alpha is functionally inactivated and NF-kappaB translocated to the nucleus. The extent of the cytotoxic effect and that of nuclear translocation of NF-kappaB show the same TNFalpha dependence. TNFalpha induces a rapid and transient activation of NF-kappaB in WEHI 164 cells which is followed by a second, long lasting phase in which the amount of NF-kappaB complex in the nucleus remains at about 50% of maximum. Upon TNFalpha treatment, IkappaB-alpha is rapidly degraded. However, newly synthesized IkappaB-alpha can be demonstrated later in the cell cytosol. A persistent nuclear localization of NF-kappaB is an obligatory step for the cytotoxic effect to take place. Thus, WEHI 164 cells treated with TNFalpha for up to 6 h can be rescued as long as NF-kappa relocalizes to the cytoplasm in its inactive form. On the other hand, TNFalpha treatments as short as 15 min cause the cytotoxic effect provided that NF-kappaB remains in the nucleus. The activation of NF-kappaB is controlled by both phosphorylation and proteolysis. The activation of NF-kappaB can be blocked by the cysteine protease inhibitor calpain inhibitor I and the serine protease inhibitor TPCK. Signal-induced phosphorylation of IkappaB-alpha does not lead to the dissociation of the inhibitor from NF-kappaB. Phosphorylation appears to regulate the inhibitory activity of IkappaB-alpha both positively and negatively. since inhibitors of protein kinases have opposite effects. Thus, treatment of cells with staurosporin induced a partial activation of NF-kappaB and was synergistic with TNFalpha induced activation. Calphostin C, on the other hand, can block the activation of NF-kappaB by TNFalpha, also blocking its proteolytic degradation.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/I-kappa B Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappaB inhibitor alpha,
http://linkedlifedata.com/resource/pubmed/chemical/Naphthalenes,
http://linkedlifedata.com/resource/pubmed/chemical/Oxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoprotein Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/calphostin C,
http://linkedlifedata.com/resource/pubmed/chemical/calyculin A
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Apr
|
| pubmed:issn |
0014-4827
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
10
|
| pubmed:volume |
224
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
63-71
|
| pubmed:dateRevised |
2007-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:8612692-Animals,
pubmed-meshheading:8612692-Base Sequence,
pubmed-meshheading:8612692-Biological Transport,
pubmed-meshheading:8612692-Cell Compartmentation,
pubmed-meshheading:8612692-Cell Nucleus,
pubmed-meshheading:8612692-DNA-Binding Proteins,
pubmed-meshheading:8612692-Enzyme Inhibitors,
pubmed-meshheading:8612692-Fibrosarcoma,
pubmed-meshheading:8612692-I-kappa B Proteins,
pubmed-meshheading:8612692-Mice,
pubmed-meshheading:8612692-Molecular Sequence Data,
pubmed-meshheading:8612692-NF-kappa B,
pubmed-meshheading:8612692-Naphthalenes,
pubmed-meshheading:8612692-Oxazoles,
pubmed-meshheading:8612692-Phosphoprotein Phosphatases,
pubmed-meshheading:8612692-Protein Binding,
pubmed-meshheading:8612692-Protein Kinase Inhibitors,
pubmed-meshheading:8612692-Tumor Cells, Cultured,
pubmed-meshheading:8612692-Tumor Necrosis Factor-alpha
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
Molecular mechanisms of TNFalpha cytotoxicity: activation of NF-kappaB and nuclear translocation.
|
| pubmed:affiliation |
Departamento de Bioquimica y Biologia Molecular, Universidad de Oviedo,Spain.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|