PMA Activates Stat3 in the Jak/Stat Pathway and Induces SOCS5 in Rat Brain Astrocytes

  • Hwang, Mi-Na (Research Institute, National Cancer Center) ;
  • Kim, Kwang Soo (Department of Pharmacology, Ajou University School of Medicine) ;
  • Choi, Yo-Woo (Research Institute, National Cancer Center) ;
  • Jou, Ilo (Department of Pharmacology, Ajou University School of Medicine) ;
  • Yoon, Sungpil (Research Institute, National Cancer Center)
  • Received : 2006.08.24
  • Accepted : 2006.12.07
  • Published : 2007.02.28

Abstract

Suppressors of cytokine signaling (SOCS) family members are negative feedback regulators of the Jak/Stat pathway, which is an essential inflammatory signaling pathway. We investigated expression of eight members of the SOCS family in rat astrocytes, using two inflammatory stimulants, PMA and IFN-${\gamma}$. Only a few SOCS genes were induced by both stimulants, and we detected an increase in SOCS5 protein with PMA. PMA activated the Jnk, Erk, p38, and Jak/Stat signal pathways. In addition, it increased the level of activated-Stat3 resulting from tyrosine phosphorylation. A gel-shift assay showed that a protein in nuclear extracts from PMA-treated cells was able to bind to Stat binding elements. These results suggest that activated Stat3 binds to SOCS promoters and leads to their transcriptional induction.

Keywords

Astrocyte;IFN-${\gamma}$;Jak/Stat;PMA;SOCS;Stat3

Acknowledgement

Supported by : National Cancer Center

References

  1. Darnell, J. E. Jr., Kerr, I. M., and Stark, G. R. (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415− 1421
  2. Frohman, E. M., Frohman, T. C., Dustin, M. L., Vayuvegula, B., Choi, B., et al. (1989) The induction of intercellular adhesion molecule 1 (ICAM-1) expression on human fetal astrocytes by interferon-gamma, tumor necrosis factor alpha, lymphotoxin, and interleukin-1: relevance to interacerabral antigen presentation. J. Neuroimmunol. 23, 117−124
  3. Igaz, P., Toth, S., and Falus, A. (2001) Biological and clinical significance of the JAK-STAT pathway; lessons from knockout mice. Inflamm. Res. 50, 435−441
  4. Kishimoto, T., Taga, T., and Akira S. (1994) Cytokine signal transduction. Cell 76, 253−262
  5. Streit, W. J., Walter, S. A., and Pennell, N. A. (1999) Reactive microgliosis. Prog. Neurobiol. 57, 563−581
  6. Wen, Z., Zhong, Z., and Darnell, J. E. Jr. (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241−250
  7. Zhou, Z. H., Chaturvedi, P., Han, Y. L., Aras, S., Li, Y. S., et al. (1998) IFN-gamma induction of the human monocyte chemoattractant protein (hMCP)-1 gene in astrocytoma cells: functional interaction between an IFN-gamma-activated site and a GC-rich element. J. Immunol. 160, 3908−3916
  8. Aeder, S. E., Martin, P. M., Soh, J. W., and Hussaini, I. M. (2004) PKC-eta mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways. Oncogene 23, 9062−9069
  9. Reid, G. A. and Schatz, G. (1982) Import of proteins into mitochondria. Extramitochondrial pools and post-translational import of mitochondrial protein precursors in vivo. J. Biol. Chem. 257, 13062−13067
  10. Vanguri, P. (1995) Interferon-gamma-inducible genes in primary glial cells of the central nervous system: comparisons of astrocytes with microglia and Lewis with brown Norway rats. J. Neuroimmunol. 56, 35−43
  11. Yang, M. S., Lee, J., Ji, K. A., Min, K. J., Lee, M. A., et al. (2004) Thrombin induces suppressor of cytokine signaling 3 expression in brain microglia via protein kinase Cdelta activation. Biochem. Biophys. Res. Commun. 317, 811−816
  12. Arai, K., Lee, S. R., and Lo, E. H. (2003) Essential role for ERK mitogen-activated protein kinase in matrix metalloproteinase- 9 regulation in rat cortical astrocytes. Glia 43, 254−264
  13. Min, K., Jou, I., and Joe, E. (2003) Plasminogen-induced IL-$1\beta$ and TNF-$\alpha$ production in microglia is regulated by reactive oxygen species. Biochem. Biophys. Res. Commun. 312, 969− 974
  14. Starr, R. and Hilton, D. J. (1999) Negative regulation of the JAK/STAT pathway. Bioessays 21, 47−52
  15. Jeon, S. B., Ji, K. A., You, H. J., Kim, J. H., Jou, I., et al. (2005) Nordihydroguariaretic acid inhibits IFN-gamma-induced STAT tyrosine phosphorylation in rat brain astrocytes. Biochem. Biophys. Res. Commun. 328, 595−600
  16. Choi, W. H., Ji, K. A., Jeon, S. B., Yang, M. S., Kim, H., et al. (2005) Anti-inflanmmatory roles of retinoic acid in rat brain astrocytes: Suppression of interferon-gamma-induced JAK/ STAT phosphorylation. Biochem. Biophys. Res. Commun. 329, 125−131
  17. Cohen, S., Dovrat, S., Sarid, R., Huberman, E., and Salzberg, S. (2005) JAK-STAT signaling involved in phorbol 12- myristate 13-acetate-and dimethyl sulfoxide-induced 2′-5′ oligoadenylate synthetase expression in human HL-60 Leukemia cells. Leuk. Res. 29, 923−931
  18. Endo, T. A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., et al. (1997) A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921−924 https://doi.org/10.1038/43219
  19. Vitkovic, L., Aloyo, V. J., Maeda, S., Benzil, D. L., Bressler, J. P., et al. (2005) Identification of myristorylated alanine-rich C kinase substrate (MARCKS) in astrocytes. Front. Biosci. 10, 160−165
  20. Chen, X. P., Losman, J. A., Cowan, S., Donahue, E., Fay, S., et al. (2002) Pim serine/threonine kinases regulate the stability of Socs-1 protein. Proc. Natl. Acad. Sci. USA 99, 2175−2180
  21. Hilton, D. J., Richardson, R. T., Alexander, W. S., Viney, E. M., Willson, T. A., et al. (1998) Twenty proteins containing a Cterminal SOCS box form five structural classes. Proc. Natl. Acad. Sci. USA 95, 114−119
  22. Hwang, J. I., Shin, K. J., Oh, Y. S., Choi, J. W., Lee, Z. W., et al. (2005) Phospholipase C-$\beta3$ mediates the thrombin-induced $Ca^{2+}$ response in glial cells. Mol. Cells 19, 375−381
  23. Ehlting, C., Haussinger, D., and Bode, J. G. (2005) Sp3 is involved in the regulation of SOCS3 gene expression. Biochem. J. 387, 737−745
  24. Amos, S., Martin, P. M., Polar, G. A., Parsons, S. J., and Hussaini, I. M. (2005) Phorbol 12-myristate 13-acetate induces epidermal growth factor receptor transactivation via protein kinase Cdelta/c-Src pathways in glioblastoma cells. J. Biol. Chem. 280, 7729−7738
  25. Ridet, J. L., Malhotra, S. K., Privat, A., and Gage, F. H. (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 20, 570−577 https://doi.org/10.1016/S0166-2236(97)85992-9
  26. Auernhammer, C. J., Bousquet, C., and Melmed, S. (1999) Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter. Proc. Natl. Acad. Sci. USA 96, 6964−6969