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

Oncogene volume 20, pages 7779–7786 (2001)Cite this article

Abstract

The serine-threonine kinase Akt exerts its anti-apoptotic effects through several downstream targets, including the pro-apoptotic Bc1-2 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 methanesulphonate. 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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References

  • Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA . 1997 J. Biol. Chem. 272: 31515–31524

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME . 1999 Cell 96: 857–868

  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC . 1998 Science 282: 1318–1321

  • Chan TO, Rittenhouse SE, Tsichlis PN . 1999 Annu. Rev. Biochem. 68: 965–1014

  • Cuddeback SM, Yamaguchi H, Komatsu K, Miyashita T, Yamada M, Wu C, Singh S, Wang H-G . 2001 J. Biol. Chem. 276: 20559–20565

  • Datta SR, Brunet A, Greenberg ME . 1999 Genes Dev. 13: 2905–2927

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME . 1997 Cell 91: 231–241

  • del Peso L, González-Garcia M, Page C, Herrera R, Nunez G . 1997 Science 278: 687–689

  • Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC . 1999 J. Cell. Biol. 144: 891–901

  • Eskes R, Desagher S, Antonsson B, Martinou JC . 2000 Mol. Cell. Biol. 20: 929–935

  • Franke TF, Cantley LC . 1997 Nature 390: 116–117

  • Franke TF, Kaplan DR, Cantley LC . 1997 Cell 88: 435–437

  • Goping IS, Gross A, Lavoie JN, Nguyen M, Jemmerson R, Roth K, Korsmeyer SJ, Shore GC . 1998 J. Cell. Biol. 143: 207–215

  • Green DR, Reed JC . 1998 Science 281: 1309–1312

  • Gross A, Jockel J, Wei MC, Korsmeyer SJ . 1998 EMBO J. 17: 3878–3885

  • Gross A, McDonnell JM, Korsmeyer SJ . 1999 Genes Dev. 13: 1899–1911

  • Heibein JA, Goping IS, Barry M, Pinkoski MJ, Shore GC, Green DR, Bleackley RC . 2000 J. Exp. Med. 192: 1391–1402

  • Hsu YT, Youle RJ . 1997 J. Biol. Chem. 272: 13829–13834

  • Hsu YT, Youle RJ . 1998 J. Biol. Chem. 273: 10777–10783

  • Hsu Y-T, Wolter KG, Youle RJ . 1997 Proc. Natl. Acad. Sci. USA 94: 3668–3672

  • Kennedy SG, Kandel ES, Cross TK, Hay N . 1999 Mol. Cell. Biol. 19: 5800–5810

  • Khwaja A . 1999 Nature 401: 33–34

  • Kuribara R, Kinoshita T, Miyajima A, Shinjyo T, Yoshihara T, Inukai T, Ozawa K, Look AT, Inaba T . 1999 Mol. Cell. Biol. 19: 2754–2762

  • Leverrier Y, Thomas J, Perkins GR, Mangeney M, Collins MK, Marvel J . 1997 Oncogene 14: 425–430

  • Li H, Zhu H, Xu CJ, Yuan J . 1998 Cell 94: 491–501

  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . 1998 Cell 94: 481–490

  • Murphy KM, Streips UN, Lock RB . 2000 J. Biol. Chem. 275: 17225–17228

  • Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y . 1998 Proc. Natl. Acad. Sci. USA 95: 14681–14686

  • Nechushtan A, Smith CL, Hsu YT, Youle RJ . 1999 EMBO J. 18: 2330–2341

  • Oltvai Z, Milliman C, Korsmeyer SJ . 1993 Cell 74: 609–619

  • Ozes ON, Mayo LD, Guston JA, Pfeffer SR, Pfeffer LM, Donner DB . 1999 Nature 401: 82–85

  • Perez D, White E . 2000 Mol. Cell. 6: 53–63

  • Porter AG . 1999 Trends Cell. Biol. 9: 394–401

  • Raff MC . 1992 Nature 356: 397–400

  • Reddy EP, Korapati A, Chaturvedi P, Rane S . 2000 Oncogene 19: 2532–2547

  • Reed JC . 1998 Oncogene 17: 3225–3236

  • Romashkova JA, Makarov SS . 1999 Nature 401: 86–90

  • Shimizu S, Narita M, Tsujimoto Y . 1999 Nature 399: 483–487

  • Songyang Z, Baltimore D, Cantley LC, Kaplan DR, Franke TF . 1997 Proc. Natl. Acad. Sci. USA 94: 11345–11350

  • Sutton VR, Davis JE, Cancilla M, Johnstone RW, Ruefli AA, Sedelies K, Browne KA, Trapani JA . 2000 J. Exp. Med. 192: 1403–1414

  • Vander Heiden MG, Thompson CB . 1999 Nat. Cell. Biol., 1: E209–E216

  • Wang H-G, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke T, Reed JC . 1999 Science 284: 339–343

  • Wang K, Yin W-M, Chao DT, Milliman CL, Korsmeyer SJ . 1996 Genes Dev. 10: 2859–2869

  • Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ . 1997 J. Cell. Biol. 139: 1281–1292

  • Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ . 1995 Cell 80: 285–291

  • Zhou H, Li XM, Meinkoth J, Pittman RN . 2000 J. Cell. Biol. 151: 483–494

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Acknowledgements

We thank Richard Youle for GFP-Bax constructs, Yun-Cai Liu for pEF-Neo vector, and the members of Flow Cytometry Core and Molecular Imaging Core at the Moffitt Cancer Center for assistance. This research was supported by NIH Grant CA82197.

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Authors and Affiliations

  1. Department of Interdisciplinary Oncology, Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, FL 33612, Florida, USA

    Hirohito Yamaguchi & Hong-Gang Wang

  2. Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, FL 33612, Florida, USA

    Hirohito Yamaguchi & Hong-Gang Wang

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  1. Hirohito Yamaguchi
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Correspondence to Hong-Gang Wang.

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Yamaguchi, H., Wang, HG. The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene 20, 7779–7786 (2001). https://doi.org/10.1038/sj.onc.1204984

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