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Regulation of reactive oxygen species, DNA damage and c-Myc function by peroxiredoxin 1

Abstract

Overexpression of c-Myc results in transformation and multiple other phenotypes and is accompanied by the deregulation of a large number of target genes. We previously demonstrated that peroxiredoxin 1 (Prdx1), a scavenger of reactive oxygen species (ROS), interacts with a region of the c-Myc transcriptional regulatory domain that is essential for transformation. This results either in the suppression or enhancement of some c-Myc functions and in the altered expression of select target genes. Most notably, c-Myc-mediated transformation is inhibited, implying a tumor suppressor role for Prdx1. Consistent with this, prdx1−/− mice develop age-dependent hemolytic anemias and/or malignancies. We now show that erythrocytes and embryonic fibroblasts from these animals contain higher levels of ROS and that the latter cells show evidence of c-Myc activation, including the ability to be transformed by a ras oncogene alone. In contrast, other primary cells from prdx1−/− mice do not have elevated ROS, but nonetheless show increased oxidative DNA damage. This apparent paradox can be explained by the fact that ROS localize primarily to the cytoplasm of prdx1+/+ cells, whereas in prdx1−/− cells, much higher levels of nuclear ROS are seen. We suggest that increased DNA damage and tumor susceptibility in prdx1−/− animals results from this shift in intracellular ROS. prdx1−/− mice should be useful in studying the role of oxidative DNA damage in the causation of cancer and its prevention by antioxidants. They should also help in studying the relationship between oncogenes such as c-Myc and DNA damage.

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References

  • Barker N, Morin PJ and Clevers H . (2000). Adv. Cancer Res., 77, 1–24.

  • Birincioglu M, Jaruga P, Chowdhury G, Rodriguez H, Dizdaroglu M and Gates KS . (2003). J. Am. Chem. Soc., 125, 11607–11615.

  • Boxer LM and Dang CV . (2001). Oncogene, 20, 5595–5610.

  • Brooks PJ, Wise DS, Berry DA, Kosmoski JV, Smerdon MJ, Somers RL, Mackie H, Spoonde AY, Ackerman EJ, Coleman K, Tarone RE and Robbins JH . (2000). J. Biol. Chem., 275, 22355–22362.

  • Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, Willi N, Mihatsch MJ, Sauter G and Kallioniemi OP . (1999). Cancer Res., 59, 803–806. Erratum in: Cancer Res. (1999) 59, 1388.

  • Cooke MS, Evans MD, Dizdaroglu M and Lunec J . (2003). FASEB J., 17, 1195–1214.

  • Coppola JA and Cole MD . (1986). Nature, 320, 760–763.

  • de Souza-Pinto NC, Eide L, Hogue BA, Thybo T, Stevnsner T, Seeberg E, Klungland A and Bohr VA . (2001). Cancer Res., 61, 5378–5381.

  • Dizdaroglu M . (1986). Biochem. J., 238, 247–254.

  • Dizdaroglu M, Jaruga P and Rodriguez H . (2001a). Nucleic Acids Res., 29, E12.

  • Dizdaroglu M, Jaruga P and Rodriguez H . (2001b). Free Radic. Biol. Med., 30, 774–784.

  • Eilers M, Schirm S and Bishop JM . (1991). EMBO J., 10, 133–141.

  • Eisenman RN . (2000-1). Harvey Lect., 96, 1–32.

  • Esposito LA, Melov S, Panov A, Cottrell BA and Wallace DC . (1999). Proc. Natl. Acad. Sci. USA, 96, 4820–4825.

  • Evan G, Harrington E, Fanidi A, Land H, Amati B and Bennett M . (1994). Philos. Trans. R. Soc. London B. Biol. Sci., 345, 269–275.

  • Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, Cocito A and Amati B . (2003). Genes Dev., 17, 1115–1129.

  • Fest T, Mougey V, Dalstein V, Hagerty M, Milette D, Silva S and Mai S . (2002). Oncogene, 21, 2981–2990.

  • Grandori C, Cowley SM, James LP and Eisenman RN . (2000). Annu. Rev. Cell Dev. Biol., 16, 653–699.

  • Grollman AP and Moriya M . (1993). Trends Genet., 9, 246–249.

  • Guschlbauer W, Duplaa AM, Guy A, Teoule R and Fazakerley GV . (1991). Nucleic Acids Res., 19, 1753–1758.

  • Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ and Wolf CR . (1998). Proc. Natl. Acad. Sci. USA, 95, 5275–5280.

  • Hironaka K, Factor VM, Calvisi DF, Conner EA and Thorgeirsson SS . (2003). Lab. Invest., 83, 643–654.

  • Henriksson M and Luscher B . (1996). Adv. Cancer Res., 68, 109–182.

  • Hofmann B, Hecht HJ and Flohe L . (2002). J. Biol. Chem., 383, 347–364.

  • Hu J, Nakano H, Sakurai H and Colburn NH . (2004). Carcinogenesis, 25, 1991–2003.

  • Iritani BM, Delrow J, Grandori C, Gomez I, Klacking M, Carlos LS and Eisenman RN . (2002). EMBO J., 21, 4820–4830.

  • Ishii T, Yamada M, Sato H, Matsue M, Taketani S, Nakayama K, Sugita Y and Bannai S . (1993). J. Biol. Chem., 268, 18633–18636.

  • Jang HH, Lee KO, Chi YH, Jung BG, Park SK, Park JH, Lee JR, Lee SS, Moon JC, Yun JW, Choi YO, Kim WY, Kang JS, Cheong GW, Yun DJ, Rhee SG, Cho MJ and Lee SY . (2004). Cell, 117, 625–635.

  • Jaruga P, Birincioglu M, Rodriguez H and Dizdaroglu M . (2002). Biochemistry, 41, 3703–3711.

  • Landay M, Oster SK, Khosravi F, Grove LE, Yin X, Sedivy J, Penn LZ and Prochownik EV . (2000). Cell Death Differ., 7, 697–705.

  • Jaruga P, Theruvathu J, Dizdaroglu M and Brooks PJ . (2004). Nucleic Acids Res., 32, e87.

  • Jaruga P, Rodriguez H and Dizdaroglu M . (2001). Free Radic. Biol. Med., 31, 336–344.

  • Johnston LA, Prober DA, Edgar BA, Eisenman RN and Gallant P . (1999). Cell, 98, 779–790.

  • Kang SW, Chae HZ, Seo MS, Kim K, Baines IC and Rhee SG . (1998). J. Biol. Chem., 273, 6297–6302.

  • Karahalil B, de Souza-Pinto NC, Parsons JL, Elder RH and Bohr VA . (2003). J. Biol. Chem., 278, 33701–33707.

  • Karlsson A, Deb-Basu D, Cherry A, Turner S, Ford J and Felsher DW . (2003). Proc. Natl. Acad. Sci. USA, 100, 9974–9979.

  • Kuraoka I, Bender C, Romieu A, Cadet J, Wood RD and Lindahl T . (2000). Proc. Natl. Acad. Sci. USA, 97, 3832–3837.

  • Kuraoka I, Robins P, Masutani C, Hanaoka F, Gasparutto D, Cadet J, Wood RD and Lindahl T . (2001). J. Biol. Chem., 276, 49283–49288.

  • Land H, Chen AC, Morgenstern JP, Parada LF and Weinberg RA . (1986). Mol. Cell. Biol., 6, 1917–1925.

  • Lasorella A, Noseda M, Beyna M, Yokota Y and Iavarone A . (2000). Nature, 407, 592–598.

  • Lee TC, Li L, Philipson L and Ziff EB . (1997). Proc. Natl. Acad. Sci. USA, 94, 12886–12891.

  • Lee TH, Kim SU, Yu SL, Kim SH, Park do S, Moon HB, Dho SH, Kwon KS, Kwon HJ, Han YH, Jeong S, Kang SW, Shin HS, Lee KK, Rhee SG and Yu DY . (2003). Blood, 101, 5033–5038.

  • Levens DL . (2003). Genes Dev., 17, 1071–1077.

  • Li LH, Nerlov C, Prendergast G, MacGregor D and Ziff EB . (1994). EMBO J., 13, 4070–4079.

  • Li Q and Dang CV . (1999). Mol. Cell. Biol., 19, 5339–5351.

  • Li Z, Van Calcar S, Qu C, Cavenee WK, Zhang MQ and Ren B . (2003). Proc. Natl. Acad. Sci. USA, 100, 8164–8169.

  • Luscher B and Larsson LG . (1999). Oncogene, 18, 2955–2966.

  • Maines JZ, Stevens LM, Tong X and Stein D . (2004). Development, 131, 775–786.

  • Marhin WW, Chen S, Facchini LM, Fornace Jr AJ and Penn LZ . (1997). Oncogene, 14, 2825–2834.

  • Marietta C, Gulam H and Brooks PJ . (2002). DNA Repair (Amsterdam)., 1, 967–975.

  • Marnett LJ, Riggins JN and West JD . (2003). J. Clin. Invest., 111, 583–593.

  • McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD and Cole MD . (1998). Cell, 94, 363–374.

  • Mikkers H and Berns A . (2003). Adv. Cancer Res., 88, 53–99.

  • Mu ZM, Yin XY and Prochownik EV . (2002). J. Biol. Chem., 277, 43175–43184.

  • Naidu R, Wahab NA, Yadav M and Kutty MK . (2002). Int. J. Mol. Med., 9, 189–196.

  • Nakahara H, Kanno T, Inai Y, Utsumi K, Hiramatsu M, Mori A and Packer L . (1998). Free Radic. Biol. Med., 24, 85–89.

  • Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH and Van Etten RA . (2003). Nature, 424, 561–565.

  • Nesbit CE, Tersak JM and Prochownik EV . (1999). MYC Oncogene, 18, 3004–3016.

  • Nikiforov MA, Chandriani S, Park J, Kotenko I, Matheos D, Johnsson A, McMahon SB and Cole MD . (2002). Mol. Cell. Biol., 22, 5054–5063.

  • Obaya AJ, Kotenko I, Cole MD and Sedivy JM . (2002). J. Biol. Chem., 277, 31263–31269.

  • Oster SK, Ho CS, Soucie EL and Penn LZ . (2002). Cancer Res., 84, 81–154.

  • Oster SK, Mao DY, Kennedy J and Penn LZ . (2003). Oncogene, 22, 1998–2010.

  • Parada LF, Land H, Chen A, Morganstern J and Weinberg RA . (1985). Prog. Med. Virol., 32, 115–128.

  • Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S and Campisi J . (2003). Nat. Cell Biol., 5, 741–747.

  • Pentland AP, Morrison AR, Jacobs SC, Hruza LL, Hebert JS and Packer L . (1992). J. Biol. Chem., 267, 15578–15584.

  • Pietilainen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM and Syrjanen K . (1995). Anticancer Res., 15, 959–964.

  • Prendergast GC . (1999). Oncogene, 18, 2967–2987.

  • Prochownik EV and Kukowska J . (1986). Nature, 322, 848–850.

  • Prochownik EV, Kukowska J and Rodgers C . (1988). Mol. Cell. Biol., 8, 3683–3695.

  • Prosperi MT, Ferbus D, Karczinski I and Goubin G . (1993). J. Biol. Chem., 268, 11050–11056.

  • Qi Y, Gregory MA, Li Z, Brousal JP, West K and Hann SR . (2004). Nature, 431, 712–717.

  • Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P and Kensler TW . (2001). Proc. Natl. Acad. Sci. USA, 98, 3410–3415.

  • Rhee SG, Chang TS, Bae YS, Lee SR and Kang SW . (2003). J. Am. Soc. Nephrol., 14, S211–S215.

  • Robertson E, Bradley A, Kuehn M and Evans M . (1986). Nature, 323, 445–448.

  • Rothermund K, Rogulski K, Fernades E, Whiting A, Sedivy J, Pu L and Prochownik EV . (2005). Cancer Res, 65, 2097–2107.

  • Sato K, Qian J, Slezak JM, Lieber MM, Bostwick DG, Bergstralh EJ and Jenkins RB . (1999). J. Natl. Cancer Inst., 91, 1574–1580.

  • Schorl C and Sedivy JM . (2003). Mol. Biol. Cell, 14, 823–835.

  • Senturker S and Dizdaroglu M . (1999). Free Radic. Biol. Med., 27, 370–380.

  • Shaul Y . (2000). Cell Death Differ., 7, 10–16.

  • Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R and Dang CV . (1997). Proc. Natl. Acad. Sci. USA, 94, 6658–6663.

  • Smith DR and Goh HS . (1996). Clin. Cancer Res., 2, 1049–1053.

  • Staller P, Peukert K, Kiermaier A, Seoane J, Lukas J, Karsunky H, Moroy T, Bartek J, Massague J, Hanel F and Eilers M . (2001). Nat. Cell Biol., 3, 392–399.

  • Stern DF, Roberts AB, Roche NS, Sporn MB and Weinberg RA . (1986). Mol. Cell. Biol., 6, 870–877.

  • Szatrowski TP and Nathan CF . (1991). Cancer Res., 51, 794–798.

  • Thorgeirsson SS, Factor VM and Snyderwine EG . (2000). Toxicol. Lett., 112–113, 553–555.

  • Toyokuni S . (1999). Pathol. Int., 49, 91–102.

  • Trzeciak AR, Nyaga SG, Jaruga P, Lohani A, Dizdaroglu M and Evans MK . (2004). Carcinogenesis, 25, 1359–1370.

  • Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM and Wahl GM . (2002). Mol. Cell, 9, 1031–1044.

  • Wang D, Kreutzer DA and Essigmann JM . (1998). Mutat Res., 400, 99–115.

  • Wanzel M, Herold S and Eilers M . (2003). Trends Cell Biol., 13, 146–150.

  • Wen ST and Van Etten RA . (1997). Genes Dev., 11, 2456–2467.

  • Wood LJ, Mukherjee M, Dolde CE, Xu Y, Maher JF, Bunton TE, Williams JB and Resar LM . (2000). Mol. Cell. Biol., 20, 5490–5502.

  • Wood ZA, Schroder E, Robin Harris J and Poole LB . (2003). Trends Biochem. Sci., 28, 32–40.

  • Xiao Q, Claassen G, Shi J, Adachi S, Sedivy J and Hann SR . (1998). Genes Dev., 12, 3803–3808.

  • Yin X, Grove L, Rogulski K and Prochownik EV . (2002). J. Biol. Chem., 277, 19998–20010.

  • Yin XY, Grove L, Datta NS, Katula K, Long MW and Prochownik EV . (2001). Cancer Res., 61, 6487–6493.

  • Yin XY, Grove L, Datta NS, Long MW and Prochownik EV . (1999). Oncogene, 18, 1177–1184.

  • Yuan L, Inoue S, Saito Y and Nakajima O . (1993). Exp. Cell Res., 209, 375–381.

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Acknowledgements

We are grateful to Dr Soo Goo Rhee for generously supplying anti-Prdx1 antibody and to Bob Lakomy for advice on fluorescence-activated cell sorting. RE was supported by NIH training Grant T32 HD042987 awarded to Children's Hospital of Pittsburgh. This work was further supported by NIH grant HL33741 awarded to EVP. Certain commercial equipment or materials are identified in this paper in order to specify adequately the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose.

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Egler, R., Fernandes, E., Rothermund, K. et al. Regulation of reactive oxygen species, DNA damage and c-Myc function by peroxiredoxin 1. Oncogene 24, 8038–8050 (2005). https://doi.org/10.1038/sj.onc.1208821

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Keywords

  • peroxiredoxin 1
  • c-Myc
  • c-Abl
  • reactive oxygen species
  • DNA damage
  • Ras
  • Omnibank®

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