Logo of biochemjBJ Latest papers and much more!
Biochem J. 2004 May 15; 380(Pt 1): 203–209.
PMCID: PMC1224164

Hypoxia/re-oxygenation-induced, redox-dependent activation of STAT1 (signal transducer and activator of transcription 1) confers resistance to apoptotic cell death via hsp70 induction.


STAT1 (signal transducer and activator of transcription 1) is potentially involved in cell survival, as well as cell death, in different types of cells. The present study was designed to examine the effects of STAT1 on hypoxia/re-oxygenation (H/R)-induced cell death and/or survival, and the underlying mechanisms of any such effects. H/R was shown to induce apoptotic cell death of rat hepatocytes. The addition of a STAT1-specific inhibitor, fludarabine, significantly increased the fraction of apoptotic cells after H/R. Following H/R, STAT1 was activated and sequential phosphorylation of Tyr701 and Ser727 was observed, which could be inhibited by the antioxidant N-acetyl-L-cysteine. Tyrosine and serine phosphorylation of STAT1 was mediated by Janus kinase 2 and phosphoinositide 3-kinase/Akt kinase respectively in a redox-dependent manner following H/R. STAT1-induced HSP70 (heat-shock protein 70) expression and the suppression of apoptosis occurred concomitantly. In conclusion, STAT1 activation, in a redox-dependent manner, following H/R may play crucial roles in cell survival, at least partly via HSP70 induction.

Full Text

The Full Text of this article is available as a PDF (474K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Ng C K Domingos, Deshpande Shailesh S, Irani Kaikobad, Alevriadou B Rita. Adhesion of flowing monocytes to hypoxia-reoxygenation-exposed endothelial cells: role of Rac1, ROS, and VCAM-1. Am J Physiol Cell Physiol. 2002 Jul;283(1):C93–102. [PubMed]
  • Nardo B, Caraceni P, Pasini P, Domenicali M, Catena F, Cavallari G, Santoni B, Maiolini E, Grattagliano I, Vendemiale G, et al. Increased generation of reactive oxygen species in isolated rat fatty liver during postischemic reoxygenation. Transplantation. 2001 Jun 27;71(12):1816–1820. [PubMed]
  • Ozaki Michitaka, Suzuki Seiichi, Irani Kaikobad. Redox factor-1/APE suppresses oxidative stress by inhibiting the rac1 GTPase. FASEB J. 2002 Jun;16(8):889–890. [PubMed]
  • Kunduzova Oxana R, Bianchi Pascale, Pizzinat Nathalie, Escourrou Ghislaine, Seguelas Marie-Helene, Parini Angelo, Cambon Claudie. Regulation of JNK/ERK activation, cell apoptosis, and tissue regeneration by monoamine oxidases after renal ischemia-reperfusion. FASEB J. 2002 Jul;16(9):1129–1131. [PubMed]
  • Chien CT, Lee PH, Chen CF, Ma MC, Lai MK, Hsu SM. De novo demonstration and co-localization of free-radical production and apoptosis formation in rat kidney subjected to ischemia/reperfusion. J Am Soc Nephrol. 2001 May;12(5):973–982. [PubMed]
  • Ozaki M, Deshpande SS, Angkeow P, Bellan J, Lowenstein CJ, Dinauer MC, Goldschmidt-Clermont PJ, Irani K. Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo. FASEB J. 2000 Feb;14(2):418–429. [PubMed]
  • Chong KY, Lai CC, Lille S, Chang C, Su CY. Stable overexpression of the constitutive form of heat shock protein 70 confers oxidative protection. J Mol Cell Cardiol. 1998 Mar;30(3):599–608. [PubMed]
  • Suzuki K, Sawa Y, Kaneda Y, Ichikawa H, Shirakura R, Matsuda H. Overexpressed heat shock protein 70 attenuates hypoxic injury in coronary endothelial cells. J Mol Cell Cardiol. 1998 Jun;30(6):1129–1136. [PubMed]
  • Dillmann WH. Heat shock proteins and protection against ischemic injury. Infect Dis Obstet Gynecol. 1999;7(1-2):55–57. [PMC free article] [PubMed]
  • Park Hee-Sae, Cho Ssang-Goo, Kim Chang Kyun, Hwang Hyun Sub, Noh Kyung Tae, Kim Mi-Sung, Huh Sung-Ho, Kim Myung Jin, Ryoo Kanghyun, Kim Eun Kyung, et al. Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1. Mol Cell Biol. 2002 Nov;22(22):7721–7730. [PMC free article] [PubMed]
  • Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM, Green DR. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol. 2000 Aug;2(8):469–475. [PubMed]
  • Garrido C, Gurbuxani S, Ravagnan L, Kroemer G. Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun. 2001 Aug 24;286(3):433–442. [PubMed]
  • Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jättelä M, Penninger JM, Garrido C, et al. Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol. 2001 Sep;3(9):839–843. [PubMed]
  • Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES. Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol. 2000 Aug;2(8):476–483. [PubMed]
  • Beresewicz A, Czarnowska E, Maczewski M. Ischemic preconditioning and superoxide dismutase protect against endothelial dysfunction and endothelium glycocalyx disruption in the postischemic guinea-pig hearts. Mol Cell Biochem. 1998 Sep;186(1-2):87–97. [PubMed]
  • Hoshida Shiro, Yamashita Nobushige, Otsu Kinya, Hori Masatsugu. The importance of manganese superoxide dismutase in delayed preconditioning: involvement of reactive oxygen species and cytokines. Cardiovasc Res. 2002 Aug 15;55(3):495–505. [PubMed]
  • Suzuki M, Takeuchi H, Kakita T, Unno M, Katayose Y, Matsuno S. The involvement of the intracellular superoxide production system in hepatic ischemia-reperfusion injury. In vivo and in vitro experiments using transgenic mice manifesting excessive CuZn-SOD activity. Free Radic Biol Med. 2000 Oct 15;29(8):756–763. [PubMed]
  • Horie Y, Wolf R, Flores SC, McCord JM, Epstein CJ, Granger DN. Transgenic mice with increased copper/zinc-superoxide dismutase activity are resistant to hepatic leukostasis and capillary no-reflow after gut ischemia/reperfusion. Circ Res. 1998 Oct 5;83(7):691–696. [PubMed]
  • Zwacka RM, Zhou W, Zhang Y, Darby CJ, Dudus L, Halldorson J, Oberley L, Engelhardt JF. Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-kappaB activation. Nat Med. 1998 Jun;4(6):698–704. [PubMed]
  • Stephanou A, Isenberg DA, Nakajima K, Latchman DS. Signal transducer and activator of transcription-1 and heat shock factor-1 interact and activate the transcription of the Hsp-70 and Hsp-90beta gene promoters. J Biol Chem. 1999 Jan 15;274(3):1723–1728. [PubMed]
  • Stephanou A, Brar BK, Scarabelli TM, Jonassen AK, Yellon DM, Marber MS, Knight RA, Latchman DS. Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis. J Biol Chem. 2000 Apr 7;275(14):10002–10008. [PubMed]
  • Stephanou A, Scarabelli TM, Brar BK, Nakanishi Y, Matsumura M, Knight RA, Latchman DS. Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701. J Biol Chem. 2001 Jul 27;276(30):28340–28347. [PubMed]
  • Madamanchi NR, Li S, Patterson C, Runge MS. Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway. Arterioscler Thromb Vasc Biol. 2001 Mar;21(3):321–326. [PubMed]
  • Minami M, Inoue M, Wei S, Takeda K, Matsumoto M, Kishimoto T, Akira S. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3963–3966. [PMC free article] [PubMed]
  • Shen Y, Devgan G, Darnell JE, Jr, Bromberg JF. Constitutively activated Stat3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Stat1. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1543–1548. [PMC free article] [PubMed]
  • Haga Sanae, Terui Keita, Zhang Hui Qi, Enosawa Shin, Ogawa Wataru, Inoue Hiroshi, Okuyama Torayuki, Takeda Kiyoshi, Akira Shizuo, Ogino Tetsuya, et al. Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms. J Clin Invest. 2003 Oct;112(7):989–998. [PMC free article] [PubMed]
  • Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997 Nov 28;278(5343):1630–1632. [PubMed]
  • Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol. 1997 Sep;17(9):5328–5337. [PMC free article] [PubMed]
  • Johnston JB, Jiang Y, van Marle G, Mayne MB, Ni W, Holden J, McArthur JC, Power C. Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity. J Virol. 2000 Aug;74(16):7211–7220. [PMC free article] [PubMed]
  • Frank DA, Mahajan S, Ritz J. Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med. 1999 Apr;5(4):444–447. [PubMed]
  • Darnell JE., Jr STATs and gene regulation. Science. 1997 Sep 12;277(5332):1630–1635. [PubMed]
  • Carballo M, Conde M, El Bekay R, Martín-Nieto J, Camacho MJ, Monteseirín J, Conde J, Bedoya FJ, Sobrino F. Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes. J Biol Chem. 1999 Jun 18;274(25):17580–17586. [PubMed]
  • Creagh EM, Carmody RJ, Cotter TG. Heat shock protein 70 inhibits caspase-dependent and -independent apoptosis in Jurkat T cells. Exp Cell Res. 2000 May 25;257(1):58–66. [PubMed]
  • Suzuki K, Sawa Y, Kagisaki K, Taketani S, Ichikawa H, Kaneda Y, Matsuda H. Reduction in myocardial apoptosis associated with overexpression of heat shock protein 70. Basic Res Cardiol. 2000 Oct;95(5):397–403. [PubMed]
  • Klein Sabine D, Brüne Bernhard. Heat-shock protein 70 attenuates nitric oxide-induced apoptosis in RAW macrophages by preventing cytochrome c release. Biochem J. 2002 Mar 15;362(Pt 3):635–641. [PMC free article] [PubMed]
  • Mazière C, Conte MA, Mazière JC. Activation of JAK2 by the oxidative stress generated with oxidized low-density lipoprotein. Free Radic Biol Med. 2001 Dec 1;31(11):1334–1340. [PubMed]
  • Abe J, Berk BC. Fyn and JAK2 mediate Ras activation by reactive oxygen species. J Biol Chem. 1999 Jul 23;274(30):21003–21010. [PubMed]
  • Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol. 1998 Dec;275(6 Pt 1):C1640–C1652. [PubMed]
  • Wang X, McCullough KD, Franke TF, Holbrook NJ. Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem. 2000 May 12;275(19):14624–14631. [PubMed]
  • Ushio-Fukai M, Alexander RW, Akers M, Yin Q, Fujio Y, Walsh K, Griendling KK. Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem. 1999 Aug 6;274(32):22699–22704. [PubMed]
  • Haddad JJ, Land SC. Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis. Br J Pharmacol. 2002 Jan;135(2):520–536. [PMC free article] [PubMed]
  • Seko Y, Takahashi N, Tobe K, Kadowaki T, Yazaki Y. Hypoxia and hypoxia/reoxygenation activate p65PAK, p38 mitogen-activated protein kinase (MAPK), and stress-activated protein kinase (SAPK) in cultured rat cardiac myocytes. Biochem Biophys Res Commun. 1997 Oct 29;239(3):840–844. [PubMed]
  • Ozaki M, Deshpande SS, Angkeow P, Suzuki S, Irani K. Rac1 regulates stress-induced, redox-dependent heat shock factor activation. J Biol Chem. 2000 Nov 10;275(45):35377–35383. [PubMed]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society


Save items

Related citations in PubMed

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...