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 (S49AR) 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 S49AR cells lacked the PtdIns(3,4,5)P3 phosphatase SHIP-1 [SH2 (Src homology 2)-domain-containing inositol phosphatase 1], a known regulator of the Akt survival pathway. Re-sensitization of the S49AR cells restored SHIP-1 expression as well as phosphoinositide and sphingomyelin levels. Knockdown of SHIP-1 mimicked the S49AR 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.
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Research Article|
October 27 2011
Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells
Maaike C. Alderliesten;
Maaike C. Alderliesten
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Jeffrey B. Klarenbeek;
Jeffrey B. Klarenbeek
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Arnold H. van der Luit;
Arnold H. van der Luit
1
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Menno van Lummel;
Menno van Lummel
2
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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David R. Jones;
David R. Jones
†Paterson Institute for Cancer Research, Inositide Laboratory, The University of Manchester, Wilmslow Road, Manchester M20 4BX, U.K.
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Shuraila Zerp;
Shuraila Zerp
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
‡Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Nullin Divecha;
Nullin Divecha
†Paterson Institute for Cancer Research, Inositide Laboratory, The University of Manchester, Wilmslow Road, Manchester M20 4BX, U.K.
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Marcel Verheij;
Marcel Verheij
‡Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Wim J. van Blitterswijk
Wim J. van Blitterswijk
3
*Division of Cell Biology (B5), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
3To whom correspondence should be addressed (email w.v.blitterswijk@nki.nl).
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Publisher: Portland Press Ltd
Received:
January 20 2011
Revision Received:
July 11 2011
Accepted:
July 27 2011
Accepted Manuscript online:
July 27 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 440 (1): 127–135.
Article history
Received:
January 20 2011
Revision Received:
July 11 2011
Accepted:
July 27 2011
Accepted Manuscript online:
July 27 2011
Citation
Maaike C. Alderliesten, Jeffrey B. Klarenbeek, Arnold H. van der Luit, Menno van Lummel, David R. Jones, Shuraila Zerp, Nullin Divecha, Marcel Verheij, Wim J. van Blitterswijk; Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells. Biochem J 15 November 2011; 440 (1): 127–135. doi: https://doi.org/10.1042/BJ20110125
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