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p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

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Abstract

Sodium arsenite induces apoptosis in PC12 cells by activating the stress-activated p38 MAP kinase and the pro-apoptotic Bcl-2 family protein BimEL. However, the relationship between p38 and BimEL in this apoptosis has not been fully defined. Here, we report that sodium arsenite stimulates the protein expression and promoter activity of BimEL in a p38-dependent manner. Sodium arsenite also caused nuclear translocation of FOXO3a, indicative of FOXO3a activation. Addition of a p38 inhibitor prevented FOXO3a nuclear translocation. RNAi knock down of FOXO3a inhibited Bim promoter activity, BimEL protein expression, and arsenite-induced apoptosis. Our data identify p38 activation of FOXO3a and subsequent induction of BimEL expression as a novel apoptotic mechanism. Together with our previous finding that BimEL is phosphorylated and activated by p38, these results demonstrate that p38 induces apoptosis by regulating BimEL at both the transcriptional and post-translational levels.

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References

  1. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, Rostami S, Jahani M, Hosseini R, Mossavi A, Baybordi E, Khodabadeh A, Iravani M et al (2006) Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol 17:131–134

    Article  PubMed  CAS  Google Scholar 

  2. Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M (2006) Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 107:2627–2632

    Article  PubMed  CAS  Google Scholar 

  3. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P et al (2001) United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19:3852–3860

    PubMed  CAS  Google Scholar 

  4. Deacon KMP, Chernoff J, Blank JL, Patel R (2003) p38 Mitogen-activated protein kinase mediates cell death and p21-activated kinase mediates cell survival during chemotherapeutic drug-induced mitotic arrest. Mol Biol Cell 14:2071–2087

    Article  PubMed  CAS  Google Scholar 

  5. Losa JH, Parada Cobo C, Viniegra JG, Sánchez-Arevalo Lobo VJ, Ramón y Cajal S, Sánchez-Prieto R (2003) Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene 22:3998–4006

    Article  PubMed  Google Scholar 

  6. Brancho D, Tanaka N, Jaeschke A, Ventura JJ, Kelkar N, Tanaka Y, Kyuuma M, Takeshita T, Flavell RA, Davis RJ (2003) Mechanism of p38 MAP kinase activation in vivo. Genes Dev 17:1969–1978

    Article  PubMed  CAS  Google Scholar 

  7. Namgung U, Xia Z (2000) Arsenite-induced apoptosis in cortical neurons is mediated by c-Jun N-terminal protein kinase 3 and p38 mitogen-activated protein kinase. J Neurosci 20:6442–6451

    PubMed  CAS  Google Scholar 

  8. Namgung U, Xia Z (2001) Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. Toxicol Appl Pharmacol 174:130–138

    Article  PubMed  CAS  Google Scholar 

  9. Cai B, Chang SH, Becker EB, Bonni A, Xia Z (2006) p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. J Biol Chem 281:25215–25222

    Article  PubMed  CAS  Google Scholar 

  10. Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629

    Article  PubMed  CAS  Google Scholar 

  11. Willis SN, Adams JM (2005) Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17(6):617–625

    Article  PubMed  CAS  Google Scholar 

  12. Molton SA, Todd DE, Cook SJ (2003) Selective activation of the c-Jun N-terminal kinase (JNK) pathway fails to elicit Bax activation or apoptosis unless the phosphoinositide 3’-kinase (PI3K) pathway is inhibited. Oncogene 22:4690–4701

    Article  PubMed  CAS  Google Scholar 

  13. Okuno SSA, Hayashi T, Chan PH (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24:7879–7887

    Article  PubMed  CAS  Google Scholar 

  14. Becker EB, Howell J, Kodama Y, Barker PA, Bonni A (2004) Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis. J Neurosci 24:8762–8770

    Article  PubMed  CAS  Google Scholar 

  15. Biswas SC, Greene LA (2002) Nerve growth factor (NGF) down-regulates the Bcl-2 homology 3 (BH3) domain-only protein Bim and suppresses its proapoptotic activity by phosphorylation. J Biol Chem 277:49511–49516

    Article  PubMed  CAS  Google Scholar 

  16. Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S, Youle RJ, LaMarche A, Maroney AC, Johnson EM Jr (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38:899–914

    Article  PubMed  CAS  Google Scholar 

  17. O’Connor L, Strasser A, O’Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC (1998) Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17:384–395

    Article  PubMed  CAS  Google Scholar 

  18. Bouillet P, Zhang LC, Huang DC, Webb GC, Bottema CD, Shore P, Eyre HJ, Sutherland GR, Adams JM (2001) Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim. Mamm Genome 12:163–168

    Article  PubMed  CAS  Google Scholar 

  19. Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A, Johnson EM (2001) Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron 29:615–628

    Article  PubMed  CAS  Google Scholar 

  20. Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J (2001) Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron 29:629–643

    Article  PubMed  CAS  Google Scholar 

  21. Essafi A, Fernández de Mattos S, Hassen YA, Soeiro I, Mufti GJ, Thomas NS, Medema RH, Lam EW (2005) Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24:2317–2329

    Article  PubMed  CAS  Google Scholar 

  22. Gilley J, Coffer PJ, Ham J (2003) FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162:613–622

    Article  PubMed  CAS  Google Scholar 

  23. Urbich C, Knau A, Fichtlscherer S, Walter DH, Bruhl T, Potente M, Hofmann WK, de Vos S, Zeiher AM, Dimmeler S (2005) FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J 19:974–976

    PubMed  CAS  Google Scholar 

  24. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331

    Article  PubMed  CAS  Google Scholar 

  25. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Article  PubMed  CAS  Google Scholar 

  26. Dérijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ (1994) JNK1: a protein kinase stimulated by uv light and HA-ras binds to and activates the c-jun activation domain. Cell 76:1025–1037

    Article  PubMed  Google Scholar 

  27. Hetman M, Kanning K, Cavanaugh JE, Xia Z (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular-signal-regulated kinase and phosphatidylinositol-3 kinase. J Biol Chem 274:22569–22580

    Article  PubMed  CAS  Google Scholar 

  28. Wang X, Finegan KG, Robinson AC, Knowles L, Khosravi-Far R, Hinchliffe KA, Boot-Handford RP, Tournier C (2006) Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress. Cell Death Differ 13:2099–2108

    Article  PubMed  CAS  Google Scholar 

  29. Sunters A, Madureira PA, Pomeranz KM, Aubert M, Brosens JJ, Cook SJ, Burgering BM, Coombes RC, Lam EW (2006) Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res 66:212–220

    Article  PubMed  CAS  Google Scholar 

  30. Tan TT, Degenhardt K, Nelson DA, Beaudoin B, Nieves-Neira W, Bouillet P, Villunger A, Adams JM, White E (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7:227–238

    Article  PubMed  CAS  Google Scholar 

  31. Egle A, Harris AW, Bouillet P, Cory S (2004) Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA 101:6164–6169

    Article  PubMed  CAS  Google Scholar 

  32. Lei K, Davis RJ (2003) JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA 100:2432–2437

    Article  PubMed  CAS  Google Scholar 

  33. Yuan J, Lipinski M, Degterev A, Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S et al (2003) Diversity in the mechanisms of neuronal cell death JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Regulation of neuronal survival and death by extracellular signals during development. Neuron 40:401–413

    Article  PubMed  CAS  Google Scholar 

  34. Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ (2003) Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem 278:18811–18816

    Article  PubMed  CAS  Google Scholar 

  35. Ley R, Ewings KE, Hadfield K, Howes E, Balmanno K, Cook SJ (2004) Extracellular signal-regulated kinases 1/2 are serum-stimulated “Bim(EL) kinases” that bind to the BH3-only protein Bim(EL) causing its phosphorylation and turnover. J Biol Chem 279:8837–8847

    Article  PubMed  CAS  Google Scholar 

  36. Harada H, Quearry B, Ruiz-Vela A, Korsmeyer SJ (2004) Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc Natl Acad Sci USA 101:15313–15317

    Article  PubMed  CAS  Google Scholar 

  37. Lu J, Quearry B, Harada H (2006) p38-MAP kinase activation followed by BIM induction is essential for glucocorticoid-induced apoptosis in lymphoblastic leukemia cells. FEBS Lett 580:3539–3544

    Article  PubMed  CAS  Google Scholar 

  38. Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, Lang JY, Lai CC, Chang CJ, Huang WC et al (2008) ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10:138–148

    Article  PubMed  CAS  Google Scholar 

  39. Liu L, Cavanaugh JE, Wang Y, Sakagami H, Mao Z, Xia Z (2003) ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons. Proc Natl Acad Sci USA 100:8532–8537

    Article  PubMed  CAS  Google Scholar 

  40. Pi X, Yan C, Berk BC (2004) Big mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. Circ Res 94:362–369

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants National Institutes of Health (NIH) R01 ES 012215 and NS44069 (ZX).

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  1. Toxicology Program, Department of Environmental and Occupational Health Sciences, University of Washington, Box 357234, Seattle, Washington, 98195-7234, USA

    Beibei Cai & Zhengui Xia

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  1. Beibei Cai
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  2. Zhengui Xia
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Correspondence to Zhengui Xia.

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Cai, B., Xia, Z. p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription. Apoptosis 13, 803–810 (2008). https://doi.org/10.1007/s10495-008-0218-5

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