Abstract
It has been suggested that oxidative stress-induced apoptosis is a major contributing factor in the pathogenesis of Alzheimer’s and Parkinson’s diseases. However, the molecular mechanism of the oxidative stress-associated apoptosis is far to be elucidated. Herein, we investigated whether STAT5, which is involved in many signaling pathways, is affected by oxidative stress. Previously, it has been shown that STAT5 is a direct activator of miR-182 which is in turn a robust inhibitor of FOXO1. Our results showed that oxidative stress inactivated STAT5 may be in a JAK2-independent manner. Thus, under oxidative stress and miR-182 down-regulation, FOXO1 has the opportunity to be translated leading to FOXO1 over-expression. Finally, pro-apoptotic gene targets of FOXO1 e.g., Bim and Bax are up-regulated leading to apoptosis. To further confirm such events, we also demonstrated that Catechin, a well-known natural antioxidant, partially restored both the STAT5 activation and miR-182 expression resulting in cell survival. To the best of our knowledge, this is the first study demonstrating that STAT5/miRNA-182 negatively regulates FOXO1 in response to oxidative stress.
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Abbreviations
- ROS:
-
Reactive oxygen species
- FOXO1:
-
Forkhead box protein O1
- STAT:
-
Signal transducers and activators of transcription
- JAK:
-
Janus tyrosine kinase
References
Sies, H. (2000). Oxidative stress: From basic research to clinical application. The American Journal of Medicine, 91, S31–S38.
Mittler, R. (2002). Oxidative stress, antioxidants and stress tolerance. Trends in Plant Science, 7, 405–410.
Baynes, J. W. (1991). Role of oxidative stress in development of complications in diabetes. Diabetes, 40, 405–412.
Coyle, J. T., & Puttfarcken, P. (1993). Oxidative stress, glutamate, and neurodegenerative disorders. Science, 262, 689–695.
Halliwell, B. (2007). Oxidative stress and cancer: have we moved forward? Biochemical Journal, 401, 1–11.
Thannickal, V. J., & Fanburg, B. L. (2000). Reactive oxygen species in cell signaling. American Journal of Physiology-Lung Cellular and Molecular Physiology., 279, L1005–L1028.
Patel, R. P., Moellering, D., Murphy-Ullrich, J., Jo, H., Beckman, J. S., & Darley-Usmar, V. M. (2000). Cell signaling by reactive nitrogen and oxygen species in atherosclerosis. Free Radical Biology and Medicine, 28, 1780–1794.
Hensley, K., Robinson, K. A., Gabbita, S. P., Salsman, S., & Floyd, R. A. (2000). Reactive oxygen species, cell signaling, and cell injury. Free Radical Biology and Medicine, 28, 1456–1462.
Ruch, R. J., Cheng, S., & Klaunig, J. E. (1989). Prevention of cytotoxicity and inhibition of intercellular communication by antioxidant catechins isolated from Chinese green tea. Carcinogenesis, 10, 1003–1008.
Leung, L. K., Su, Y., Chen, R., Zhang, Z., Huang, Y., & Chen, Z. Y. (2001). Theaflavins in black tea and catechins in green tea are equally effective antioxidants. The Journal of nutrition., 131, 2248–2251.
Mandel, S., Amit, T., Reznichenko, L., Weinreb, O., & Youdim, M. B. H. (2006). Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Molecular Nutrition & Food Research, 50, 229–234.
Rawlings, J. S., Rosler, K. M., & Harrison, D. A. (2004). The JAK/STAT signaling pathway. Journal of Cell Science, 117, 1281–1283.
Gamero, A. M., & Larner, A. C. (2001). Vanadate facilitates interferon α-mediated apoptosis that is dependent on the Jak/Stat pathway. Journal of Biological Chemistry, 276, 13547–13553.
Weber-Nordt, R., Mertelsmann, R., & Finke, J. (1998). The JAK-STAT pathway: signal transduction involved in proliferation, differentiation and transformation. Leukemia & lymphoma., 28, 459–467.
Lu, Y., Zhou, J., Xu, C., Lin, H., Xiao, J., Wang, Z., et al. (2008). JAK/STAT and PI3 K/AKT pathways form a mutual transactivation loop and afford resistance to oxidative stress-induced apoptosis in cardiomyocytes. Cellular Physiology and Biochemistry, 21, 305–314.
Simon, A. R., Rai, U., Fanburg, B. L., & Cochran, B. H. (1998). Activation of the JAK-STAT pathway by reactive oxygen species. American Journal of Physiology-Cell Physiology., 275, C1640–C1652.
Mazière, C., Conte, M. A., & Mazière, J. C. (2001). Activation of JAK2 by the oxidative stress generated with oxidized low-density lipoprotein. Free Radical Biology and Medicine, 31, 1334–1340.
Sandberg, E. M., & Sayeski, P. P. (2004). Jak2 tyrosine kinase mediates oxidative stress-induced apoptosis in vascular smooth muscle cells. Journal of Biological Chemistry, 279, 34547–34552.
Madamanchi, N. R., Li, S., Patterson, C., & Runge, M. S. (2001). Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 21, 321–326.
Yu, H., Zhi, J., Cui, Y., Tang, E., Sun, S., Feng, J., et al. (2006). Role of the JAK-STAT pathway in protection of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress in PC12 cells. Apoptosis, 11, 931–941.
Buitenhuis, M., Coffer, P. J., & Koenderman, L. (2004). Signal transducer and activator of transcription 5 (STAT5). The international journal of biochemistry & cell biology., 36, 2120–2124.
Ambrosio, R., Fimiani, G., Monfregola, J., Sanzari, E., De Felice, N., Salerno, M. C., et al. (2002). The structure of human STAT5A and B genes reveals two regions of nearly identical sequence and an alternative tissue specific STAT5B promoter. Gene, 285, 311–318.
Socolovsky, M., Fallon, A. E. J., Wang, S., Brugnara, C., & Lodish, H. F. (1999). Fetal anemia and apoptosis of red cell progenitors in Stat5a/5b mice: A direct role for Stat5 in Bcl-XL induction. Cell, 98, 181–191.
Lord, J. D., McIntosh, B. C., Greenberg, P. D., & Nelson, B. H. (2000). The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. The Journal of Immunology, 164, 2533–2541.
Dudley, A. C., Thomas, D., Best, J., & Jenkins, A. (2004). The STATs in cell stress-type responses. Cell Communication and Signaling, 2, 8–13.
Debierre-Grockiego, F. (2004). Anti-apoptotic role of STAT5 in haematopoietic cells and in the pathogenesis of malignancies. Apoptosis, 9, 717–728.
Inui, M., Martello, G., & Piccolo, S. (2010). MicroRNA control of signal transduction. Nature Reviews Molecular Cell Biology, 11, 252–263.
Kim, V. N., Han, J., & Siomi, M. C. (2009). Biogenesis of small RNAs in animals. Nature Reviews Molecular Cell Biology, 10, 126–139.
Stark, A., Brennecke, J., Bushati, N., Russell, R. B., & Cohen, S. M. (2005). Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3′ UTR evolution. Cell, 123, 1133–1146.
Griffiths-Jones, S. (2010). miRBase: microRNA sequences and annotation. Current Protocols in Bioinformatics., 12, 1–12.
Miska, E. A. (2005). How microRNAs control cell division, differentiation and death. Current Opinion in Genetics & Development, 15, 563–568.
Li, G., Miskimen, K. L., Wang, Z., Xie, X. Y., Brenzovich, J., Ryan, J. J., et al. (2010). STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease. Blood, 115, 1416–1424.
O’Neill, L. A. J. (2010). Outfoxing Foxo1 with miR-182. Nature Immunology, 11, 983–984.
Stittrich, A. B., Haftmann, C., Sgouroudis, E., Kühl, A. A., Hegazy, A. N., Panse, I., et al. (2010). The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nature Immunology, 11, 1057–1062.
Guttilla, I. K., & White, B. A. (2009). Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. Journal of Biological Chemistry, 284, 23204–23216.
Furukawa-Hibi, Y., Kobayashi, Y., Chen, C., & Motoyama, N. (2005). FOXO transcription factors in cell-cycle regulation and the response to oxidative stress. Antioxidants & Redox Signaling, 7, 752–760.
Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Castrillon, D. H., Cullen, D. E., et al. (2007). FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell, 128, 325–339.
Gheysarzadeh, A., & Yazdanparast, R. (2012). Inhibition Of H 2O 2 Induced Cell Death Through Foxo1 Modulation By Euk-172 In Sk-N-Mc Cells. European Journal of Pharmacology, 697, 47–52.
D’Autréaux, B., & Toledano, M. B. (2007). ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nature Reviews Molecular Cell Biology, 8, 813–824.
Choi, W. S., Eom, D. S., Han, B. S., Kim, W. K., Han, B. H., Choi, E. J., et al. (2004). Phosphorylation of p38 MAPK induced by oxidative stress is linked to activation of both caspase-8-and-9-mediated apoptotic pathways in dopaminergic neurons. Journal of Biological Chemistry, 279, 20451–20460.
Raza, H., & John, A. (2007). In vitro protection of reactive oxygen species-induced degradation of lipids, proteins and 2-deoxyribose by tea catechins. Food and Chemical Toxicology, 45, 1814–1820.
Ihle, J. N. (2001). The Stat family in cytokine signaling. Current Opinion in Cell Biology, 13, 211–217.
Nosaka, T., Kawashima, T., Misawa, K., Ikuta, K., Mui, A. L. F., & Kitamura, T. (1999). STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. The EMBO Journal., 18, 4754–4765.
Byts, N., Samoylenko, A., Fasshauer, T., Ivanisevic, M., Hennighausen, L., Ehrenreich, H., et al. (2008). Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin. Cell Death and Differentiation, 15, 783–792.
Cholez, E., Debuysscher, V., Bourgeais, J., Boudot, C., Leprince, J., Tron, F., et al. (2012). Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells. Leukemia, 26(11), 2390–2397.
Shimoda, K., Feng, J., Murakami, H., Nagata, S., Watling, D., Rogers, N. C., et al. (1997). Jak1 plays an essential role for receptor phosphorylation and Stat activation in response to granulocyte colony-stimulating factor. Blood, 90, 597–604.
Caffarel, M. M., Zaragoza, R., Pensa, S., Li, J., Green, A. R., & Watson, C. J. (2011). Constitutive activation of JAK2 in mammary epithelium elevates Stat5 signalling, promotes alveologenesis and resistance to cell death, and contributes to tumourigenesis. Cell Death and Differentiation, 19, 511–522.
Kirken, R. A., Rui, H., Malabarba, M. G., Howard, O., Kawamura, M., O’Shea, J. J., et al. (1995). Activation of JAK3, but not JAK1, is critical for IL-2-induced proliferation and STAT5 recruitment by a COOH-terminal region of the IL-2 receptor beta-chain. Cytokine, 7, 689–700.
Moskwa, P., Buffa, F. M., Pan, Y., Panchakshari, R., Gottipati, P., Muschel, R. J., et al. (2011). miR-182-mediated down-regulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Molecular Cell, 41, 210–220.
Zhang, L., Liu, T., Huang, Y., & Liu, J. (2011). microRNA-182 inhibits the proliferation and invasion of human lung adenocarcinoma cells through its effect on human cortical actin-associated protein. International Journal of Molecular Medicine, 28, 381–388.
Segura, M. F., Hanniford, D., Menendez, S., Reavie, L., Zou, X., Alvarez-Diaz, S., et al. (2009). Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proceedings of the National Academy of Sciences, 106, 1814–1819.
Lam, E., Francis, R., & Petkovic, M. (2006). FOXO transcription factors: key regulators of cell fate. Biochemical Society Transactions, 34, 722–726.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193, 265–275.
Abmayr, S. M., Carrozza, M. J., & Workman, J. L. (2003). Preparation of nuclear and cytoplasmic extracts from mammalian cells. Current protocols in pharmacology. John Wiley, 12(1), 1.
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2-[Delta][Delta] CT method. Methods, 25, 402–408.
Chen, C., Ridzon, D. A., Broomer, A. J., Zhou, Z., Lee, D. H., Nguyen, J. T., et al. (2005). Real-time quantification of microRNAs by stem–loop RT–PCR. Nucleic Acids Research, 33, e179–e179.
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The authors appreciate the financial support of this investigation by the Research Council of University of Tehran.
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Gheysarzadeh, A., Yazdanparast, R. STAT5 Reactivation by Catechin Modulates H2O2-Induced Apoptosis Through miR-182/FOXO1 Pathway in SK-N-MC Cells. Cell Biochem Biophys 71, 649–656 (2015). https://doi.org/10.1007/s12013-014-0244-6
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DOI: https://doi.org/10.1007/s12013-014-0244-6