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FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity

Survival signals elicited by cytokines include the activation of phosphatidylinositol 3-kinase (PI3K), which in turn promotes the activation of protein kinase B (PKB). Recently, PKB has been demonstrated to phosphorylate and inactivate forkhead transcription factor FKHR-L1, a potent inducer of apopt...

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Autores principales: Dijkers, Pascale F., Birkenkamp, Kim U., Lam, Eric W.-F., Thomas, N. Shaun B., Lammers, Jan-Willem J., Koenderman, Leo, Coffer, Paul J.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173339/
https://www.ncbi.nlm.nih.gov/pubmed/11815629
http://dx.doi.org/10.1083/jcb.200108084
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author Dijkers, Pascale F.
Birkenkamp, Kim U.
Lam, Eric W.-F.
Thomas, N. Shaun B.
Lammers, Jan-Willem J.
Koenderman, Leo
Coffer, Paul J.
author_facet Dijkers, Pascale F.
Birkenkamp, Kim U.
Lam, Eric W.-F.
Thomas, N. Shaun B.
Lammers, Jan-Willem J.
Koenderman, Leo
Coffer, Paul J.
author_sort Dijkers, Pascale F.
collection PubMed
description Survival signals elicited by cytokines include the activation of phosphatidylinositol 3-kinase (PI3K), which in turn promotes the activation of protein kinase B (PKB). Recently, PKB has been demonstrated to phosphorylate and inactivate forkhead transcription factor FKHR-L1, a potent inducer of apoptosis. To explore the mechanisms underlying the induction of apoptosis after cytokine withdrawal or FKHR-L1 activation, we used a cell line in which FKHR-L1 activity could be specifically induced. Both cytokine withdrawal and FKHR-L1 activation induced apoptosis, which was preceded by an upregulation in p27(KIP1) and a concomitant decrease in cells entering the cell cycle. Induction of apoptosis by both cytokine withdrawal and activation of FKHR-L1 correlated with the disruption of mitochondrial membrane integrity and cytochrome c release. This was preceded by upregulation of the pro-apoptotic Bcl-2 family member Bim. Ectopic expression of an inhibitory mutant of FKHR-L1 substantially reduced the levels of apoptosis observed after cytokine withdrawal. Activation of PKB alone was sufficient to promote cell survival, as measured by maintenance of mitochondrial integrity and the resultant inhibition of effector caspases. Furthermore, hematopoietic stem cells isolated from Bim(−/−) mice exhibited reduced levels of apoptosis upon inhibition of PI3K/PKB signaling. These data demonstrate that activation of FKHR-L1 alone can recapitulate all known elements of the apoptotic program normally induced by cytokine withdrawal. Thus PI3K/PKB–mediated inhibition of this transcription factor likely provides an important mechanism by which survival factors act to prevent programmed cell death.
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spelling pubmed-21733392008-05-01 FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity Dijkers, Pascale F. Birkenkamp, Kim U. Lam, Eric W.-F. Thomas, N. Shaun B. Lammers, Jan-Willem J. Koenderman, Leo Coffer, Paul J. J Cell Biol Article Survival signals elicited by cytokines include the activation of phosphatidylinositol 3-kinase (PI3K), which in turn promotes the activation of protein kinase B (PKB). Recently, PKB has been demonstrated to phosphorylate and inactivate forkhead transcription factor FKHR-L1, a potent inducer of apoptosis. To explore the mechanisms underlying the induction of apoptosis after cytokine withdrawal or FKHR-L1 activation, we used a cell line in which FKHR-L1 activity could be specifically induced. Both cytokine withdrawal and FKHR-L1 activation induced apoptosis, which was preceded by an upregulation in p27(KIP1) and a concomitant decrease in cells entering the cell cycle. Induction of apoptosis by both cytokine withdrawal and activation of FKHR-L1 correlated with the disruption of mitochondrial membrane integrity and cytochrome c release. This was preceded by upregulation of the pro-apoptotic Bcl-2 family member Bim. Ectopic expression of an inhibitory mutant of FKHR-L1 substantially reduced the levels of apoptosis observed after cytokine withdrawal. Activation of PKB alone was sufficient to promote cell survival, as measured by maintenance of mitochondrial integrity and the resultant inhibition of effector caspases. Furthermore, hematopoietic stem cells isolated from Bim(−/−) mice exhibited reduced levels of apoptosis upon inhibition of PI3K/PKB signaling. These data demonstrate that activation of FKHR-L1 alone can recapitulate all known elements of the apoptotic program normally induced by cytokine withdrawal. Thus PI3K/PKB–mediated inhibition of this transcription factor likely provides an important mechanism by which survival factors act to prevent programmed cell death. The Rockefeller University Press 2002-02-04 /pmc/articles/PMC2173339/ /pubmed/11815629 http://dx.doi.org/10.1083/jcb.200108084 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Dijkers, Pascale F.
Birkenkamp, Kim U.
Lam, Eric W.-F.
Thomas, N. Shaun B.
Lammers, Jan-Willem J.
Koenderman, Leo
Coffer, Paul J.
FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity
title FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity
title_full FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity
title_fullStr FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity
title_full_unstemmed FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity
title_short FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity
title_sort fkhr-l1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase b–enhanced cell survival through maintenance of mitochondrial integrity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173339/
https://www.ncbi.nlm.nih.gov/pubmed/11815629
http://dx.doi.org/10.1083/jcb.200108084
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