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Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma

Oncogene volume 29, pages 4938–4946 (2010)Cite this article

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Abstract

Chemoresistance is a major cause of treatment failure and poor outcome in neuroblastoma. In this study, we investigated the expression and function of dual-specificity phosphatase 26 (DUSP26), also known as mitogen-activated protein kinase phophatase-8, in human neuroblastoma. We found that DUSP26 was expressed in a majority of neuroblastoma cell lines and tissue specimens. Importantly, we found that DUSP26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis. In contrast, DUSP26 overexpression in the SK-N-SH cell line inhibited doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression and apoptosis. Using in vitro and in vivo assays, we found that DUSP26 binds to p53 and dephosphorylates p53 at Ser20 and Ser37. In this report, we show that DUSP26 functions as a p53 phosphatase, which suppresses downstream p53 activity in response to genotoxic stress. This suggests that inhibition of this phosphatase may increase neuroblastoma chemosensitivity and DUSP26 is a novel therapeutic target for this aggressive pediatric malignancy.

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References

  • Amano T, Nakamizo A, Mishra SK, Gumin J, Shinojima N, Sawaya R et al. (2009). Simultaneous phosphorylation of p53 at serine 15 and 20 induces apoptosis in human glioma cells by increasing expression of pro-apoptotic genes. J Neurooncol 92: 357–371.

    Article  CAS  Google Scholar 

  • Brodeur GM . (2003). Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3: 203–216.

    Article  CAS  Google Scholar 

  • Brooks CL, Gu W . (2003). Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol 15: 164–171.

    Article  CAS  Google Scholar 

  • Chehnab NH, Malikazy A, Stravridi ES, Halazonetis TD . (1999). Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc Natl Acad Sci USA 96: 13777–13782.

    Article  Google Scholar 

  • Chen L, Malcolm AJ, Wood KM, Cole M, Variend S, Cullinane C et al. (2007). p53 is nuclear and functional in both undifferentiated and differentiated neuroblastoma. Cell Cycle 6: 2685–2696.

    Article  CAS  Google Scholar 

  • Eischen CM, Lozano G . (2009). p53 and MDM2: antagonists or partners in crime? Cancer Cell 15: 161–162.

    Article  CAS  Google Scholar 

  • Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A . (2003). Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am J Pathol 162: 1807–1815.

    Article  CAS  Google Scholar 

  • Goldman SC, Chen CY, Lowsing TJ, Gilmer TM, Kastan MB . (1996). The p53 signal transduction pathway is intact in human neuroblastoma despite cytoplasmic localization. Am J Pathol 148: 1381–1385.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hupp TR, Lane DP, Ball KL . (2000). Strategies for manipulating the p53 pathway in the treatment of human cancer. Biochem J 352 (Part 1): 1–17.

    Article  CAS  Google Scholar 

  • Jeffrey KL, Camps M, Rommel C, Mackay CR . (2007). Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov 6: 391–403.

    Article  CAS  Google Scholar 

  • Kruse JP, Gu W . (2009). Modes of p53 regulation. Cell 137: 609–622.

    Article  CAS  Google Scholar 

  • Levine AJ . (1997). p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.

    Article  CAS  Google Scholar 

  • Li DW, Liu JP, Schmid PC, Schlosser R, Feng H, Liu WB et al. (2006). Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities. Oncogene 25: 3006–3022.

    Article  CAS  Google Scholar 

  • Li L, Ljungman M, Dixon JE . (2000). The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53. J Biol Chem 275: 2410–2414.

    Article  CAS  Google Scholar 

  • London WB, Castleberry RP, Matthay KK, Look AT, Seeger RC, Shimada H et al. (2005). Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23: 6459–6465.

    Article  CAS  Google Scholar 

  • Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE et al. (1994). p53 status and the efficacy of cancer therapy in vivo. Science 266: 807–810.

    Article  CAS  Google Scholar 

  • Lu X, Nannenga B, Donehower LA . (2005). PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev 19: 1162–1174.

    Article  CAS  Google Scholar 

  • Maruta H, Holden J, Sizeland A, D'Abaco G . (1991). The residues of Ras and Rap proteins that determine their GAP specificities. J Biol Chem 266: 11661–11668.

    CAS  PubMed  Google Scholar 

  • Matthay KK, Perez C, Seeger RC, Brodeur GM, Shimada H, Atkinson JB et al. (1998). Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J Clin Oncol 16: 1256–1264.

    Article  CAS  Google Scholar 

  • Moll UM, LaQuaglia M, Benard J, Riou G . (1995). Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. Proc Natl Acad Sci USA 92: 4407–4411.

    Article  CAS  Google Scholar 

  • Patterson KI, Brummer T, O'Brien PM, Daly RJ . (2009). Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 418: 475–489.

    Article  CAS  Google Scholar 

  • Pestell KE, Ducruet AP, Wipf P, Lazo JS . (2000). Small molecule inhibitors of dual specificity protein phosphatases. Oncogene 19: 6607–6612.

    Article  CAS  Google Scholar 

  • Shang X, Burlingame SM, Okcu MF, Ge N, Russell HV, Egler RA et al. (2009). Aurora A is a negative prognostic factor and a new therapeutic target in human neuroblastoma. Mol Cancer Ther 8: 2461–2469.

    Article  CAS  Google Scholar 

  • Slack A, Chen Z, Tonelli R, Pule M, Hunt L, Pession A et al. (2005). The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc Natl Acad Sci USA 102: 731–736.

    Article  CAS  Google Scholar 

  • Toledo F, Wahl GM . (2006). Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6: 909–923.

    Article  CAS  Google Scholar 

  • Tweddle DA, Malcolm AJ, Bown N, Pearson AD, Lunec J . (2001). Evidence for the development of p53 mutations after cytotoxic therapy in a neuroblastoma cell line. Cancer Res 61: 8–13.

    CAS  PubMed  Google Scholar 

  • Tweddle DA, Pearson AD, Haber M, Norris MD, Xue C, Flemming C et al. (2003). The p53 pathway and its inactivation in neuroblastoma. Cancer Lett 197: 93–98.

    Article  CAS  Google Scholar 

  • Unger T, Juven-Gershon T, Moallem E, Berger M, Vogt Sionov R, Lozano G et al. (1999). Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. EMBO J 18: 1805–1814.

    Article  CAS  Google Scholar 

  • Vasudevan SA, Skoko J, Wang K, Burlingame SM, Patel PN, Lazo JS et al. (2005). MKP-8, a novel MAPK phosphatase that inhibits p38 kinase. Biochem Biophys Res Commun 330: 511–518.

    Article  CAS  Google Scholar 

  • Vasudevan SA, Shang X, Chang S, Ge N, Diaz-Miron JL, Russel HV et al. (2009). Neuroblastoma derived secretory protein is a novel secreted factor overexpressed in neuroblastoma. Mol Cancer Ther 8: 2478–2489.

    Article  CAS  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ . (2000). Surfing the p53 network. Nature 408: 307–310.

    Article  CAS  Google Scholar 

  • Vousden KH, Lu X . (2002). Live or let die: the cell's response to p53. Nat Rev Cancer 2: 594–604.

    Article  CAS  Google Scholar 

  • Yu W, Imoto I, Inoue J, Onda M, Emi M, Inazawa J . (2007). A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene 26: 1178–1187.

    Article  CAS  Google Scholar 

  • Yu Y, Ge N, Xie M, Sun W, Burlingame S, Pass AK et al. (2008). Phosphorylation of Thr-178 and Thr- 184 in the TAK1 T-loop is required for interleukin (IL)-1-mediated optimal NFkappaB and AP-1 activation as well as IL-6 gene expression. J Biol Chem 283: 24497–24505.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Xiangwei Wu for providing GFP-p53 expression plasmid and Mdm2-Luc reporter. The work was supported in part by the grants from the Hope Street Kids Foundation (to JY), the Bear Necessities Pediatric Cancer Foundation (to JY), the American Cancer Society Grant RSG-06-070-01-TBE (to JY), the Society of University Surgeons Ethicon Resident Scholarship (SAV) and the NIH/NCI-NRSA training grant 1F32CA113059-01A1 (SAV).

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Author notes

  1. X Shang and S A Vasudevan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Texas Children's Cancer Center, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    X Shang, Y Yu, N Ge, A D Ludwig, K Wang, S M Burlingame, Y-j Zhao, P H Rao, H V Russell, M F Okcu, J M Shohet, J G Nuchtern & J Yang

  2. Michael E DeBakey Department of Surgery, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    X Shang, S A Vasudevan, C L Wesson, S M Burlingame & J G Nuchtern

  3. Department of Biological Sciences, University of South Carolina, Columbia, SC, USA

    X Lu

  4. Department of Pathology, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    M J Hicks

  5. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA

    L A Donehower

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  1. X Shang
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Correspondence to J G Nuchtern or J Yang.

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Shang, X., Vasudevan, S., Yu, Y. et al. Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma. Oncogene 29, 4938–4946 (2010). https://doi.org/10.1038/onc.2010.244

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