The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change

Hirohito Yamaguchi, Hong-Gang Wang

Research output: Contribution to journalArticle

295 Citations (Scopus)

Abstract

The serine-threonine kinase Akt exerts its anti-apoptotic effects through several downstream targets, including the pro-apoptotic Bcl-2 family member Bad, Forkhead transcription factors, and the cyclic AMP response element-binding protein (CREB). In this report we demonstrate that Akt inhibits a conformational change in the pro-apoptotic Bax protein and its translocation to mitochondria, thus preventing the disruption of the mitochondrial inner membrane potential (ΔΨm), caspase-3 activation, and apoptosis in pre-B hematopoietic cells FL5.12 following interleukin-3 (IL-3) withdrawal. Inhibition of PI-3 kinase, but not MAPK kinase, promotes this conformational change in Bax. Moreover, overexpression of Akt suppresses the relocalization of GFP-Bax to mitochondria and apoptosis in Hela cells induced by the DNA-damaging agent methyl methane-sulphonate. However, Akt does not abolish the ability of a conformationally changed Bax mutant, GFP-Bax (ΔS184), to translocate to mitochondria and to induce apoptosis. These findings indicate that Akt exerts its anti-apoptotic effects in cells at a premitochondrial stage, at least in part, by inhibiting Bax conformational change and its redistribution to the mitochondrial membranes.

Original languageEnglish (US)
Pages (from-to)7779-7786
Number of pages8
JournalOncogene
Volume20
Issue number53
DOIs
StatePublished - Nov 22 2001

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Protein Kinases
Cell Survival
Mitochondria
Apoptosis
Forkhead Transcription Factors
bcl-2-Associated X Protein
Cyclic AMP Response Element-Binding Protein
Apoptosis Regulatory Proteins
Aptitude
B-Lymphoid Precursor Cells
Mitochondrial Membrane Potential
Interleukin-3
Protein-Serine-Threonine Kinases
Mitogen-Activated Protein Kinase Kinases
Methane
Mitochondrial Membranes
Protein Transport
Phosphatidylinositol 3-Kinases
HeLa Cells
Caspase 3

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

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abstract = "The serine-threonine kinase Akt exerts its anti-apoptotic effects through several downstream targets, including the pro-apoptotic Bcl-2 family member Bad, Forkhead transcription factors, and the cyclic AMP response element-binding protein (CREB). In this report we demonstrate that Akt inhibits a conformational change in the pro-apoptotic Bax protein and its translocation to mitochondria, thus preventing the disruption of the mitochondrial inner membrane potential (ΔΨm), caspase-3 activation, and apoptosis in pre-B hematopoietic cells FL5.12 following interleukin-3 (IL-3) withdrawal. Inhibition of PI-3 kinase, but not MAPK kinase, promotes this conformational change in Bax. Moreover, overexpression of Akt suppresses the relocalization of GFP-Bax to mitochondria and apoptosis in Hela cells induced by the DNA-damaging agent methyl methane-sulphonate. However, Akt does not abolish the ability of a conformationally changed Bax mutant, GFP-Bax (ΔS184), to translocate to mitochondria and to induce apoptosis. These findings indicate that Akt exerts its anti-apoptotic effects in cells at a premitochondrial stage, at least in part, by inhibiting Bax conformational change and its redistribution to the mitochondrial membranes.",
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The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. / Yamaguchi, Hirohito; Wang, Hong-Gang.

In: Oncogene, Vol. 20, No. 53, 22.11.2001, p. 7779-7786.

Research output: Contribution to journalArticle

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