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

doi:10.1083/jcb.200108084

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Published online 28 January 2002. doi:10.1083/jcb.200108084

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© The Rockefeller University Press, 0021-9525/2002/2/531 $5.00
The Journal of Cell Biology, Volume 156, Number 3, February 4, 2002 531-542

Article

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

Pascale F. Dijkers¹, Kim U. Birkenkamp¹, Eric W.-F. Lam², N. Shaun B. Thomas³, Jan-Willem J. Lammers¹, Leo Koenderman¹ and Paul J. Coffer¹

¹ Department of Pulmonary Diseases, University Medical Center, 3584 CX Utrecht, Netherlands
² CRC Labs and Section of Cancer Cell Biology, Imperial College School of Medicine at Hammersmith Hospital, London W12 ONN, UK
³ Guy's, King's, St. Thomas's School of Medicine and Dentistry, The Rayne Institute, London SE5 9NU, UK

Address correspondence to Paul J. Coffer, Department of Pulmonary Diseases, G03.550, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, Netherlands. Tel.: 31-30-250-7134. Fax: 31-30-250-5414. E-mail: p.coffer{at}hli.azu.nl

Survival signals elicited by cytokines include the activationof phosphatidylinositol 3-kinase (PI3K), which in turn promotesthe activation of protein kinase B (PKB). Recently, PKB hasbeen demonstrated to phosphorylate and inactivate forkhead transcriptionfactor FKHR-L1, a potent inducer of apoptosis. To explore themechanisms underlying the induction of apoptosis after cytokinewithdrawal or FKHR-L1 activation, we used a cell line in whichFKHR-L1 activity could be specifically induced. Both cytokinewithdrawal and FKHR-L1 activation induced apoptosis, which waspreceded by an upregulation in p27^KIP1 and a concomitant decreasein cells entering the cell cycle. Induction of apoptosis byboth cytokine withdrawal and activation of FKHR-L1 correlatedwith the disruption of mitochondrial membrane integrity andcytochrome c release. This was preceded by upregulation of thepro-apoptotic Bcl-2 family member Bim. Ectopic expression ofan inhibitory mutant of FKHR-L1 substantially reduced the levelsof apoptosis observed after cytokine withdrawal. Activationof PKB alone was sufficient to promote cell survival, as measuredby maintenance of mitochondrial integrity and the resultantinhibition of effector caspases. Furthermore, hematopoieticstem cells isolated from Bim^-/- mice exhibited reduced levelsof apoptosis upon inhibition of PI3K/PKB signaling.

These data demonstrate that activation of FKHR-L1 alone canrecapitulate all known elements of the apoptotic program normallyinduced by cytokine withdrawal. Thus PI3K/PKB–mediatedinhibition of this transcription factor likely provides an importantmechanism by which survival factors act to prevent programmedcell death.

Key Words: apoptosis; cytokine; mitochondria; PI3K; forkhead

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