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p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils

Alvarado-Kristensson, Maria (author)
Lund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Molekylär patologi, Malmö,Experimental Pathology, Malmö,Lund University Research Groups,Molecular Pathology, Malmö
Melander, Fredrik (author)
Lund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Experimental Pathology, Malmö,Lund University Research Groups
Leandersson, Karin (author)
Lund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Experimental Pathology, Malmö,Lund University Research Groups
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Rönnstrand, Lars (author)
Lund University,Lunds universitet,Institutionen för translationell medicin,Medicinska fakulteten,Department of Translational Medicine,Faculty of Medicine
Wernstedt, Christer (author)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Andersson, Tommy (author)
Lund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Experimental Pathology, Malmö,Lund University Research Groups
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 (creator_code:org_t)
2004-02-17
2004
English.
In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 199:4, s. 449-458
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Neutrophil apoptosis occurs both in the bloodstream and in the tissue and is considered essential for the resolution of an inflammatory process. Here, we show that p38-mitogen-activated protein kinase (MAPK) associates to caspase-8 and caspase-3 during neutrophil apoptosis and that p38-MAPK activity, previously shown to be a survival signal in these primary cells, correlates with the levels of caspase-8 and caspase-3 phosphorylation. In in vitro experiments, immunoprecipitated active p38-MAPK phosphorylated and inhibited the activity of the active p20 subunits of caspase-8 and caspase-3. Phosphopeptide mapping revealed that these phosphorylations occurred on serine-364 and serine-150, respectively. Introduction of mutated (S150A), but not wild-type, TAT-tagged caspase-3 into primary neutrophils made the Fas-induced apoptotic response insensitive to p38-MAPK inhibition. Consequently, p38-MAPK can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Keyword

Apoptosis
Caspases/antagonists & inhibitors/*blood
Cell Survival/physiology
Humans
Inflammation/blood
Mitogen-Activated Protein Kinases/*blood
Neutrophils/cytology/*enzymology
Phosphorylation
Research Support; Non-U.S. Gov't
Signal Transduction/physiology
p38 Mitogen-Activated Protein Kinases

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