Altered lipid raft composition and defective cell death signal transduction in glycosylphosphatidylinositol anchor-deficient PIG-A mutant cells.
Br J Haematol
; 142(3): 413-22, 2008 Jul.
Article
en En
| MEDLINE
| ID: mdl-18544084
ABSTRACT
Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal disorder of haematopoietic stem cells caused by somatic PIGA mutations, resulting in a deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-AP). Because GPI-AP associate with lipid rafts (LR), lack of GPI-AP on PNH cells may result in alterations in LR-dependent signalling. Conversely, PNH cells are a suitable model for investigating LR biology. LR from paired, wild-type GPI(+), and mutant GPI(-) cell lines (K562 and TF1) were isolated and analysed; GPI(-) LR contained important anti-apoptotic proteins, not found in LR from GPI(+) cells. When methyl-beta-cyclodextrin (MbetaCD) was utilized to probe for functional differences between normal and GPI(-) LR, increased levels of phospho-p38 mitogen-activated protein kinase (MAPK), and phospho-p65 nuclear factor NF-kappaB were found in control and GPI(-) cells respectively. Subsequent experiments addressing the inhibition of phosphoinositide-3-kinase (PI3K) suggest that the PI3K/AKT pathway may be responsible for the resistance of K562 GPI(-)cells to negative effects of MbetaCD. In addition, transduction of tumour necrosis factor-alpha (TNF-alpha) signals in a LR-dependent fashion increased induction of p38 MAPK in GPI(+) and increased pro-survival NF-kappaB levels in K562 GPI(-) cells. Therefore, we suggest that the altered LR-dependent signalling in PNH-like cells may induce different responses to pro-inflammatory cytokines from those observed in cells with intact GPI-AP.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células Madre Hematopoyéticas
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Glicosilfosfatidilinositoles
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Microdominios de Membrana
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Hemoglobinuria Paroxística
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Proteínas de la Membrana
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Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2008
Tipo del documento:
Article