title: Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells.
abstract: S49 mouse lymphoma cells undergo apoptosis in response to the ALP (alkyl-lysophospholipid) edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine), FasL (Fas ligand) and DNA damage. S49 cells made resistant to ALP (S49(AR)) are defective in sphingomyelin synthesis and ALP uptake, and also have acquired resistance to FasL and DNA damage. However, these cells can be re-sensitized following prolonged culturing in the absence of ALP. The resistant cells show sustained ERK (extracellular-signal-regulated kinase)/Akt activity, consistent with enhanced survival signalling. In search of a common mediator of the observed cross-resistance, we found that S49(AR) cells lacked the PtdIns(3,4,5)P(3) phosphatase SHIP-1 [SH2 (Src homology 2)-domain-containing inositol phosphatase 1], a known regulator of the Akt survival pathway. Re-sensitization of the S49(AR) cells restored SHIP-1 expression as well as phosphoinositide and sphingomyelin levels. Knockdown of SHIP-1 mimicked the S49(AR) phenotype in terms of apoptosis cross-resistance, sphingomyelin deficiency and altered phosphoinositide levels. Collectively, the results of the present study suggest that SHIP-1 collaborates with sphingomyelin synthase to regulate lymphoma cell death irrespective of the nature of the apoptotic stimulus.
authors.affiliation: Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Maaike C
authors.initials: MC
authors.lastname: Alderliesten
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Klarenbeek
authors.forename: Arnold H
authors.initials: AH
authors.lastname: van der Luit
authors.forename: Menno
authors.initials: M
authors.lastname: van Lummel
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Shuraila
authors.initials: S
authors.lastname: Zerp
authors.forename: Nullin
authors.initials: N
authors.lastname: Divecha
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.forename: Wim J
authors.initials: WJ
authors.lastname: van Blitterswijk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D008223:Lymphoma / Q000473:pathology; D051379:Mice; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010742:Phospholipid Ethers / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D018129:Phosphatidylinositol Phosphates; D010742:Phospholipid Ethers; C060974:phosphatidylinositol 3,4,5-triphosphate; C026659:edelfosine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C556686:Sgms1 protein, mouse; D017855:Transferases (Other Substituted Phosphate Groups); D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases