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SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis


Suppressors of cytokine signaling (SOCS) are negative regulators of cytokine-induced signal transduction, which play multiple roles in cell growth, differentiation and apoptosis. In this study, the regulatory role of SOCS in oxidative stress-induced apoptosis was investigated. In Jurkat T cells and mouse splenocytes, we have found that SOCS1 is induced in response to tumor necrosis factor-α or H2O2, concomitant with the activation of Jaks which act as important mediators of reactive oxygen species (ROS)-induced apoptosis upstream of p38 mitogen-activated protein kinase. Using SOCS1 overexpressing or knockdown Jurkat T-cell systems we clearly demonstrate that, SOCS1 inhibits the ROS-mediated apoptosis. The antiapoptotic action of SOCS1 was exerted not only by suppressing Jaks, but also by sustaining protein tyrosine phosphatase (PTP) activities. Notably, SOCS1-transduced cells displayed increase in thioredoxin levels and decrease in ROS generation induced by oxidative stress. In addition, the Jak-inhibiting and PTP-sustaining effect of SOCS1 was significantly reduced on thioredoxin ablation. Moreover, coimmunoprecipitation data revealed molecular interaction of SHP1 or CD45 with thioredoxin, which was promoted in SOCS1-transfected cells. Together, our data strongly suggest that both the protection of PTPs by thioredoxin from ROS attack and the attenuation of Jaks account for the antiapoptotic function of SOCS1 in immune cells under oxidative stress.

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2′,7′-dichlorodihydrofluorescein diacetate; Jak,Janus tyrosine kinase


protein tyrosine phosphatase


reactive oxygen species


small hairpin RNA


small interference RNA


suppressors of cytokine signaling


signal transducers and activators of transcription




  • Alexander WS . (2002). Suppressors of cytokine signaling (SOCS) in the immune system. Nat Rev Immunol 2: 410–416.

    Article  CAS  Google Scholar 

  • Baetz A, Koelsche C, Strebovsky J, Heeg K, Dalpke AH . (2008). Identification of a nuclear localization signal in suppressor of cytokine signaling 1. FASEB J 22: 4296–4305.

    Article  CAS  Google Scholar 

  • Barrett DM, Black SM, Todor H, Schmidt-Ullrich RK, Dawson KS, Mikkelsen RB . (2005). Inhibition of protein-tyrosine phosphatases by mild oxidative stresses is dependent on S-nitrosylation. J Biol Chem 280: 14453–14461.

    Article  CAS  Google Scholar 

  • Cao Q, Mak KM, Ren C, Lieber CS . (2004). Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependant MAPK pathways. J Biol Chem 279: 4292–4304.

    Article  CAS  Google Scholar 

  • Chong MM, Thomas HE, Kay TW . (2002). Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor. J Biol Chem 277: 27945–27952.

    Article  CAS  Google Scholar 

  • Cuncic C, Detich N, Ethier D, Tracey AS, Gresser MJ, Ramachandran C . (1999). Vanadate inhibition of protein tyrosine phosphatases in Jurkat cells: modulation by redox state. J Biol Inorg Chem 4: 354–359.

    Article  CAS  Google Scholar 

  • Dang PM, Stensballe A, Boussetta T, Raad H, Dewas C, Kroviarski Y et al. (2006). A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. J Clin Invest 116: 2033–2043.

    Article  CAS  Google Scholar 

  • Denu JM, Tanner KG . (1998). Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 37: 5633–5642.

    Article  CAS  Google Scholar 

  • Devadas S, Zaritskaya L, Rhee SG, Oberley L, Williams MS . (2002). Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. J Exp Med 195: 59–70.

    Article  CAS  Google Scholar 

  • Didier C, Kerblat I, Drouet C, Favier A, Beani JC, Richard MJ . (2001). Induction of thioredoxin by ultraviolet-A radiation prevents oxidative-mediated cell death in human skin fibroblasts. Free Radic Biol Med 31: 585–598.

    Article  CAS  Google Scholar 

  • Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K et al. (1997). A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387: 921–924.

    Article  CAS  Google Scholar 

  • Fialkow L, Chan CK, Grinstein S, Downey GP . (1993). Regulation of tyrosine phosphorylation in neutrophils by the NADPH oxidase. Role of reactive oxygen intermediates. J Biol Chem 268: 17131–17137.

    CAS  PubMed  Google Scholar 

  • Han SI, Kim YS, Kim TH . (2008). Role of apoptotic and necrotic cell death under physiological conditions. J Biochem Mol Biol 41: 1–10.

    CAS  Google Scholar 

  • He Y, Zhang W, Zhang R, Zhang H, Min W . (2006). SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation. J Biol Chem 281: 5559–5566.

    Article  CAS  Google Scholar 

  • Hsieh CC, Papaconstantinou J . (2006). Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. FASEB J 20: 259–268.

    Article  CAS  Google Scholar 

  • Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G et al. (2001). CD45 is a JAK phosphatase and negatively regulates cytokine receptor signaling. Nature 409: 349–354.

    Article  CAS  Google Scholar 

  • Jang JY, Lee CE . (2006). IL-4-induced upregulation of adenine nucleotide translocase 3 and its role in Th cell survival from apoptosis. Cell Immunol 241: 14–25.

    Article  CAS  Google Scholar 

  • Jeon BN, Yoo JY, Choi WI, Lee CE, Yoon HG, Hur MW . (2008). Proto-oncogene FBI-1(Pokemon/ZBTB7A) represses transcription of tumor suppressor Rb gene via binding competition with SP1 and recruitment of corepressors. J Biol Chem 283: 33199–323210.

    Article  CAS  Google Scholar 

  • Jeong SY, Seol DW . (2008). The role of mitochondria in apoptosis. J Biochem Mol Biol 41: 11–22.

    CAS  Google Scholar 

  • Kim BJ, Ryu SW, Song BJ . (2006). JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 281: 21256–21265.

    Article  CAS  Google Scholar 

  • Kim SH, Oh J, Choi JY, Jang JY, Kang MW, Lee CE . (2008). Identification of human thioredoxin as a novel IFN-gamma-induced factor: mechanism of induction and its role in cytokine production. BMC Immunol 9: 64.

    Article  Google Scholar 

  • Kimura A, Naka T, Nagata S, Kawase I, Kishimoto T . (2004). SOCS-1 suppresses TNF-alpha-induced apoptosis through the regulation of Jak activation. Int Immunol 16: 991–999.

    Article  CAS  Google Scholar 

  • Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M et al. (2002). SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17: 583–591.

    Article  CAS  Google Scholar 

  • Kubo M, Hanada T, Yoshimura A . (2003). Suppressors of cytokine signaling and immunity. Nat Immunol 4: 1169–1176.

    Article  CAS  Google Scholar 

  • Lee K, Esselman WJ . (2002). Inhibition of PTPs by H2O2 regulates the activation of distinct MAPK pathways. Free Radic Biol Med 33: 1121–1132.

    Article  CAS  Google Scholar 

  • Masuhiro Y, Kayama K, Fukushima A, Baba K, Soutsu M, Kamiya Y et al. (2008). SOCS-3 inhibits E2F/DP-1 transcriptional activity and cell cycle progression via interaction with DP-1. J Biol Chem 283: 31575–31583.

    Article  CAS  Google Scholar 

  • Morita Y, Naka T, Kawazoe Y, Fujimoto M, Narazaki M, Nakagawa R et al. (2000). Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor alpha-induced cell death in fibroblasts. Proc Natl Acad Sci USA 97: 5405–5410.

    Article  CAS  Google Scholar 

  • Nakamura H, Nakamura K, Yodoi J . (1997). Redox regulation of cellular activation. Annu Rev Immunol 15: 351–369.

    Article  CAS  Google Scholar 

  • Nordberg J, Arner ES . (2001). Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31: 1287–1312.

    Article  CAS  Google Scholar 

  • Odaka C, Mizuochi T, Yang J, Ding A . (2003). Murine macrophages produce secretory leukocyte protease inhibitor during clearance of apoptotic cells: implications for resolution of the inflammatory response. J Immunol 171: 1507–1514.

    Article  CAS  Google Scholar 

  • Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K et al. (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22: 153–183.

    CAS  PubMed  Google Scholar 

  • Penninger JM, Irie-Sasaki J, Sasaki T, Oliveira-dos-Santos AJ . (2001). CD45: new jobs for an old acquaintance. Nat Immunol 2: 389–396.

    Article  CAS  Google Scholar 

  • Reth M . (2002). Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol 3: 1129–1134.

    Article  CAS  Google Scholar 

  • Rusanescu G, Yang W, Bai A, Neel BG, Feig LA . (2005). Tyrosine phosphatase SHP-2 is a mediator of activity-dependent neuronal excitotoxicity. EMBO J 24: 305–314.

    Article  CAS  Google Scholar 

  • Sparwasser T, Miethke T, Lipford G, Erdmann A, Hacker H, Heeg K et al. (1997). Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor-alpha-mediated shock. Eur J Immunol 27: 1671–1679.

    Article  CAS  Google Scholar 

  • To KF, Chan MW, Leung WK, Ng EK, Yu J, Bai AH et al. (2004). Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line. Br J Cancer 91: 1335–1341.

    Article  CAS  Google Scholar 

  • Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T et al. (1999). The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J 18: 1309–1320.

    Article  CAS  Google Scholar 

  • Yoshida T, Ogata H, Kamio M, Joo A, Shiraishi H, Tokunaga Y et al. (2004). SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis. J Exp Med 199: 1701–1707.

    Article  CAS  Google Scholar 

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This work was supported by Brain Korea 21 program and research grants from KOSEF (2008-01752), KRF (314-2008-1:E00030) and MOHW (A084298). J Oh was supported in part by the 2005 Seoul Graduate Student Scholarship.

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Correspondence to C-E Lee.

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Oh, J., Hur, MW. & Lee, CE. SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis. Oncogene 28, 3145–3156 (2009).

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