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PKA/Smurf1 signaling-mediated stabilization of Nur77 is required for anticancer drug cisplatin-induced apoptosis

Oncogene volume 33, pages 1629–1639 (2014)Cite this article

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Abstract

The orphan nuclear receptor Nur77 regulates diverse cellular activities, including cell proliferation, differentiation and apoptosis. The c-Jun N-terminal kinase (JNK) have a dual role in controlling the function of Nur77. While JNK-mediated phosphorylation of Nur77 positively regulates its translocation to the mitochondria to induce apoptosis, it negatively regulates the stability of Nur77. The underlying mechanism for the dual role of JNK in regulating Nur77, however, is unclear. Here, we report that E3 ubiquitin ligase Smad ubiquitination regulatory factor 1 (Smurf1) prevents Nur77 degradation through mediating its unconventional ubiquitination, thereby mitigating the JNK-mediated downregulating effect, which leads to Nur77 accumulation and subsequent translocation to mitochondria to trigger apoptosis. In this process, protein kinase A (PKA)-mediated phosphorylation of Smurf1 at Thr306 is a prerequisite step. Accordingly, cyclic AMP/PKA signaling switches the fate of Nur77 from degradation to triggering apoptosis in chemotherapy drug cisplatin-treated cells. Hence, our study revealed a novel mechanism, by which PKA/Smurf1 antagonizes the downregulating effect of JNK on Nur77, leading to the accumulation of Nur77 for apoptosis induction triggered by cisplatin.

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References

  1. Pearen MA, Muscat GE . Minireview: nuclear hormone receptor 4A signaling: implications for metabolic disease. Mol Endocrinol 2010; 24: 1891–1903.

    Article  CAS  Google Scholar 

  2. Liu ZG, Smith SW, McLaughlin KA, Schwartz LM, Osborne BA . Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77. Nature 1994; 367: 281–284.

    Article  CAS  Google Scholar 

  3. Woronicz JD, Calnan B, Ngo V, Winoto A . Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 1994; 367: 277–281.

    Article  CAS  Google Scholar 

  4. Lee SO, Li X, Khan S, Safe S . Targeting NR4A1 (TR3) in cancer cells and tumors. Expert Opin Ther Targets 2011; 15: 195–206.

    Article  Google Scholar 

  5. Yao LM, He JP, Chen HZ, Wang Y, Wang WJ, Wu R et al. Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis. Carcinogenesis 2012; 33: 301–311.

    Article  CAS  Google Scholar 

  6. Yu H, Kumar SM, Fang D, Acs G, Xu X . Nuclear orphan receptor TR3/Nur77 mediates melanoma cell apoptosis. Cancer Biol Ther 2007; 6: 405–412.

    Article  CAS  Google Scholar 

  7. Holmes WF, Soprano DR, Soprano KJ . Early events in the induction of apoptosis in ovarian carcinoma cells by CD437: activation of the p38 MAP kinase signal pathway. Oncogene 2003; 22: 6377–6386.

    Article  CAS  Google Scholar 

  8. Liu JJ, Zeng HN, Zhang LR, Zhan YY, Chen Y, Wang Y et al. A unique pharmacophore for activation of the nuclear orphan receptor Nur77 in vivo and in vitro. Cancer Res 2010; 70: 3628–3637.

    Article  CAS  Google Scholar 

  9. Yang H, Zhan Q, Wan YJ . Enrichment of Nur77 mediated by retinoic acid receptor beta leads to apoptosis of human hepatocellular carcinoma cells induced by fenretinide and histone deacetylase inhibitors. Hepatology 2011; 53: 865–874.

    Article  CAS  Google Scholar 

  10. Yoon K, Lee SO, Cho SD, Kim K, Khan S, Safe S . Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors. Carcinogenesis 2011; 32: 836–842.

    Article  CAS  Google Scholar 

  11. Han YH, Cao X, Lin B, Lin F, Kolluri SK, Stebbins J et al. Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt. Oncogene 2006; 25: 2974–2986.

    Article  CAS  Google Scholar 

  12. Jacobs CM, Boldingh KA, Slagsvold HH, Thoresen GH, Paulsen RE . ERK2 prohibits apoptosis-induced subcellular translocation of orphan nuclear receptor NGFI-B/TR3. J Biol Chem 2004; 279: 50097–50101.

    Article  CAS  Google Scholar 

  13. Masuyama N, Oishi K, Mori Y, Ueno T, Takahama Y, Gotoh Y . Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis. J Biol Chem 2001; 276: 32799–32805.

    Article  CAS  Google Scholar 

  14. Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y et al. Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Proc Natl Acad Sci USA 2001; 98: 3690–3694.

    Article  CAS  Google Scholar 

  15. Wang A, Rud J, Olson Jr. CM, Anguita J, Osborne BA . Phosphorylation of Nur77 by the MEK-ERK-RSK cascade induces mitochondrial translocation and apoptosis in T cells. J Immunol 2009; 183: 3268–3277.

    Article  CAS  Google Scholar 

  16. Wingate AD, Campbell DG, Peggie M, Arthur JS . Nur77 is phosphorylated in cells by RSK in response to mitogenic stimulation. Biochem J 2006; 393: 715–724.

    Article  CAS  Google Scholar 

  17. Hirata Y, Kiuchi K, Chen HC, Milbrandt J, Guroff G . The phosphorylation and DNA binding of the DNA-binding domain of the orphan nuclear receptor NGFI-B. J Biol Chem 1993; 268: 24808–24812.

    CAS  PubMed  Google Scholar 

  18. Chen HZ, Liu QF, Li L, Wang WJ, Yao LM, Yang M et al. The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling. Gut 2012; 61: 714–724.

    Article  CAS  Google Scholar 

  19. Moll UM, Marchenko N, Zhang XK . p53 and Nur77/TR3—transcription factors that directly target mitochondria for cell death induction. Oncogene 2006; 25: 4725–4743.

    Article  CAS  Google Scholar 

  20. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 2004; 116: 527–540.

    Article  CAS  Google Scholar 

  21. Liu B, Wu JF, Zhan YY, Chen HZ, Zhang XY, Wu Q . Regulation of the orphan receptor TR3 nuclear functions by c-Jun N terminal kinase phosphorylation. Endocrinology 2007; 148: 34–44.

    Article  CAS  Google Scholar 

  22. Hazel TG, Misra R, Davis IJ, Greenberg ME, Lau LF . Nur77 is differentially modified in PC12 cells upon membrane depolarization and growth factor treatment. Mol Cell Biol 1991; 11: 3239–3246.

    Article  CAS  Google Scholar 

  23. Izzi L, Attisano L . Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation. Oncogene 2004; 23: 2071–2078.

    Article  CAS  Google Scholar 

  24. Cheng PL, Lu H, Shelly M, Gao H, Poo MM . Phosphorylation of E3 ligase Smurf1 switches its substrate preference in support of axon development. Neuron 2011; 69: 231–243.

    Article  CAS  Google Scholar 

  25. Jin YH, Jeon EJ, Li QL, Lee YH, Choi JK, Kim WJ et al. Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. J Biol Chem 2004; 279: 29409–29417.

    Article  CAS  Google Scholar 

  26. Narimatsu M, Bose R, Pye M, Zhang L, Miller B, Ching P et al. Regulation of planar cell polarity by Smurf ubiquitin ligases. Cell 2009; 137: 295–307.

    Article  CAS  Google Scholar 

  27. Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL . Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 2005; 307: 1603–1609.

    Article  CAS  Google Scholar 

  28. Schwamborn JC, Muller M, Becker AH, Puschel AW . Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity. EMBO J 2007; 26: 1410–1422.

    Article  CAS  Google Scholar 

  29. Wang HR, Zhang Y, Ozdamar B, Ogunjimi AA, Alexandrova E, Thomsen GH et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 2003; 302: 1775–1779.

    Article  CAS  Google Scholar 

  30. Yamashita M, Ying SX, Zhang GM, Li C, Cheng SY, Deng CX et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell 2005; 121: 101–113.

    Article  CAS  Google Scholar 

  31. Zhao M, Qiao M, Oyajobi BO, Mundy GR, Chen D . E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem 2003; 278: 27939–27944.

    Article  CAS  Google Scholar 

  32. Hoeller D, Hecker CM, Dikic I . Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 2006; 6: 776–788.

    Article  CAS  Google Scholar 

  33. Kulathu Y, Komander D . Atypical ubiquitylation—the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol 2012; 13: 508–523.

    Article  CAS  Google Scholar 

  34. Insel PA, Zhang L, Murray F, Yokouchi H, Zambon AC . Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger. Acta Physiol (Oxf) 2012; 204: 277–287.

    Article  CAS  Google Scholar 

  35. Zambon AC, Zhang L, Minovitsky S, Kanter JR, Prabhakar S, Salomonis N et al. Gene expression patterns define key transcriptional events in cell-cycle regulation by cAMP and protein kinase A. Proc Natl Acad Sci USA 2005; 102: 8561–8566.

    Article  CAS  Google Scholar 

  36. Zhang L, Zambon AC, Vranizan K, Pothula K, Conklin BR, Insel PA . Gene expression signatures of cAMP/protein kinase A (PKA)-promoted, mitochondrial-dependent apoptosis. Comparative analysis of wild-type and cAMP-deathless S49 lymphoma cells. J Biol Chem 2008; 283: 4304–4313.

    Article  CAS  Google Scholar 

  37. Nie J, Xie P, Liu L, Xing G, Chang Z, Yin Y et al. Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes p53 degradation by stabilizing the E3 ligase MDM2. J Biol Chem 2010; 285: 22818–22830.

    Article  CAS  Google Scholar 

  38. Popov N, Schulein C, Jaenicke LA, Eilers M . Ubiquitylation of the amino terminus of Myc by SCF(beta-TrCP) antagonizes SCF(Fbw7)-mediated turnover. Nat Cell Biol 2010; 12: 973–981.

    Article  CAS  Google Scholar 

  39. Lebwohl D, Canetta R . Clinical development of platinum complexes in cancer therapy: an historical perspective and an update. Eur J Cancer 1998; 34: 1522–1534.

    Article  CAS  Google Scholar 

  40. Kartalou M, Essigmann JM . Mechanisms of resistance to cisplatin. Mutat Res 2001; 478: 23–43.

    Article  CAS  Google Scholar 

  41. Cepeda V, Fuertes MA, Castilla J, Alonso C, Quevedo C, Perez JM . Biochemical mechanisms of cisplatin cytotoxicity. Anticancer Agents Med Chem 2007; 7: 3–18.

    Article  CAS  Google Scholar 

  42. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O et al. Molecular mechanisms of cisplatin resistance. Oncogene 2012; 31: 1869–1883.

    Article  CAS  Google Scholar 

  43. Wiesner S, Ogunjimi AA, Wang HR, Rotin D, Sicheri F, Wrana JL et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain. Cell 2007; 130: 651–662.

    Article  CAS  Google Scholar 

  44. Hsu SC, Wu CC, Han J, Lai MZ . Involvement of p38 mitogen-activated protein kinase in different stages of thymocyte development. Blood 2003; 101: 970–976.

    Article  CAS  Google Scholar 

  45. Sanna MG, da Silva Correia J, Ducrey O, Lee J, Nomoto K, Schrantz N et al. IAP suppression of apoptosis involves distinct mechanisms: the TAK1/JNK1 signaling cascade and caspase inhibition. Mol Cell Biol 2002; 22: 1754–1766.

    Article  CAS  Google Scholar 

  46. Clegg CH, Correll LA, Cadd GG, McKnight GS . Inhibition of intracellular cAMP-dependent protein kinase using mutant genes of the regulatory type I subunit. J Biol Chem 1987; 262: 13111–13119.

    CAS  PubMed  Google Scholar 

  47. Wang HR, Ogunjimi AA, Zhang Y, Ozdamar B, Bose R, Wrana JL . Degradation of RhoA by Smurf1 ubiquitin ligase. Methods Enzymol 2006; 406: 437–447.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Ministry of Science and Technology of China (2011CB910800), the National Natural Science Foundation of China (31070771, 30970614, 81272248), the Fundamental Research Funds for the Central Universities (2010121087), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20090121120017) and Project 111 sponsored by the State Bureau of Foreign Experts and Ministry of Education (B12001). We thank SC Lin for commenting on the manuscript.

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  1. H Lin, Q Lin and M Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China

    H Lin, Q Lin, M Liu, Y Lin, X Wang, H Chen, F Ding, Q Wu & H-R Wang

  2. Life Sciences Institute and College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Z Xia

  3. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    B Lu

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Lin, H., Lin, Q., Liu, M. et al. PKA/Smurf1 signaling-mediated stabilization of Nur77 is required for anticancer drug cisplatin-induced apoptosis. Oncogene 33, 1629–1639 (2014). https://doi.org/10.1038/onc.2013.116

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