생명과학회지 (Journal of Life Science)

  • 제22권11호
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  • Pages.1500-1506
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  • 2012
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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TGF-β에 의한 간세포의 세포사멸 과정에서 SGK1 발현 감소의 중요성

Downregulation of SGK1 Expression is Critical for TGF-β-induced Apoptosis in Mouse Hepatocytes Cells

  • 남인구 (경상대학교 자연과학대학 미생물학과/생명과학연구원) ;
  • 유지윤 (경상대학교 자연과학대학 미생물학과/생명과학연구원)
  • Nam, In-Koo (Department of Microbiology/Research Institute of Life Science, College of Natural Sciences, Gyeongsang National University) ;
  • Yoo, Jiyun (Department of Microbiology/Research Institute of Life Science, College of Natural Sciences, Gyeongsang National University)
  • 투고 : 2012.09.05
  • 심사 : 2012.11.21
  • 발행 : 2012.11.30
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초록

Transforming growth factor-${\beta}$ (TGF-${\beta}$)에 의해 유도되는 세포사멸 과정은 간에서 손상 받은 조직이나 비정상적인 조직을 제거하는데 중요한 역할을 담당한다. 간세포에서 TGF-${\beta}$에 의해 유도되는 세포사멸 과정 동안 중요한 기능을 담당하는 유전자를 탐색하고자 쥐의 간세포인 AML12 세포를 이용하여 TGF-${\beta}$ 처리 전후에 발현이 변화되는 유전자를 microarray analysis를 통해 확인하였다. TGF-${\beta}$에 의해 여러 가지 유전자들의 발현이 변화됨을 확인하였는데, 그 가운데 여러 가지 세포사멸 인자들의 활성을 억제하여 세포사멸을 억제한다고 알려져 있는 SGK1의 발현 감소를 확인하였다. TGF-${\beta}$에 의해 SGK1의 mRNA와 단백질 level이 모두 감소함을 확인하였고, 항상 active한 형태의 SGK1 (CA-SGK1)을 발현시켰을 때 TGF-${\beta}$에 의한 세포사멸이 억제됨을 확인하였다. 이러한 결과들은 간세포에서 SGK1의 발현 감소가 TGF-${\beta}$에 의한 세포사멸을 유도하는데 중요한 기능을 담당할 가능성이 높음을 의미하는 것이다.

Transforming growth factor (TGF)-${\beta}$-dependent apoptosis is important in the elimination of damaged or abnormal cells from normal tissues, especially in liver, in vivo. To investigate which gene expressions are critical for TGF-${\beta}$-induced apoptosis in hepatocytes, gene expression profiling experiments were performed with TGF-${\beta}$-treated and non-treated mouse hepatocytes AML12 cells. Findings showed that serum and glucocorticoid-inducible protein kinase1 (SGK1) expression is markedly downregulated during TGF-${\beta}$-induced apoptosis. Findings confirmed that expression of SGK1 protein, as well as mRNA, is also markedly decreased with TGF-${\beta}$ treatment. Infection of adenoviral vector encoding constitutively active SGK1 (CA-SGK1), but not kinase dead SGK1 (KD-SGK1), attenuated TGF-${\beta}$-induced apoptosis. All of these results suggest that downregulation of SGK1 expression is critical for TGF-${\beta}$-induced apoptosis in AML12 cells.

키워드

참고문헌

  1. Chen, R. H. and Chang, T. Y. 1997. Involvement of Caspase family proteases in transforming growth factor-beta-induced apoptosis. Cell Growth Differ. 8, 821-827.
  2. Fukuchi, Y., Kizaki, M., Yamato, K., Kawamura, C., Umezawa, A., Hata, J., Nishihara, T. and Ikeda, Y. 2001. Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells. Oncogene 20, 704-713. https://doi.org/10.1038/sj.onc.1204142
  3. Fukuda, K., Kojiro, M. and Chiu, J. F. 1993. Induction of apoptosis by transforming growth factor-beta 1 in the rat hepatoma cell line McA-RH7777: a possible association with tissue transglutaminase expression. Hepatology 18, 945-953. https://doi.org/10.1002/hep.1840180428
  4. Hsu, W. L., Chiu, T. H., Tai, D. J., Ma, Y. L. and Lee, E. H. 2009. A novel defense mechanism that is activated on amyloid-beta insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling. Cell Death Differ. 16, 1515-1529. https://doi.org/10.1038/cdd.2009.91
  5. Ikushima, H. and Miyazono, K. 2011. Biology of transforming growth factor-beta signaling. Curr. Pharm. Biotechnol. 12, 2099-2107. https://doi.org/10.2174/138920111798808419
  6. Jang, C. W., Chen, C. H., Chen, C. C., Chen, J. Y., Su, Y. H. and Chen, R. H. 2002. TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat. Cell Biol. 4, 51-58. https://doi.org/10.1038/ncb731
  7. Koseki, T., Yamato, K., Krajewski, S., Reed, J. C., Tsujimoto, Y. and Nishihara, T. 1995. Activin A-induced apoptosis is suppressed by BCL-2. FEBS Lett. 376, 247-250. https://doi.org/10.1016/0014-5793(95)01290-7
  8. Lan, H. Y. and Chung, A. C. 2011. Transfroming growth factor-beta and Smads. Contrib. Nephrol. 170, 75-82. https://doi.org/10.1159/000324949
  9. Larisch, S., Yi, Y., Lotan, R., Kerner, H., Eimeri, S., Tony Parks, W., Gottfried, Y., Birkey Reffey, S., de Caestecker, M. P., Danielpour, D., Book-Melamed, N., Timberg, R., Duckett, C. S., Lechleider, R. J., Steller, H., Orly, J., Kim, S. J. and Roberts, A. B. 2000. A novel mitochondrial septin- like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nat. Cell Biol. 2, 915-921. https://doi.org/10.1038/35046566
  10. Lin, J. K. and Chou, C. K. 1992. In vivo apoptosis in the human hepatoma-cell line induced by transforming growth factor-beta1. Cancer Res. 52, 385-388.
  11. Melhem, A., Yamada, S. D., Fleming, G. F., Delgado, B., Brickley, D. R., Wu, W., Kocherginsky, M. and Conzen, S. D. 2009. Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues. Clin. Cancer Res. 15, 3196-3204. https://doi.org/10.1158/1078-0432.CCR-08-2131
  12. Meulmeester, E. and ten Dijke, P. 2011. The dynamic roles of TGF-beta in cancer. J. Pathol. 223, 205-218.
  13. Oberhammer, F., Bursch, W., Tiefenbacher, R., Froschl, G., Pavelka, M., Purchio, T. and Schulte-Hermann, R. 1993. Apoptosis is induced by transforming growth factor-beta1 within 5 hours in regressing liver without significant fragmentation of the DNA. Hepatology 18, 1238-1246. https://doi.org/10.1002/hep.1840180533
  14. Pardali, K. and Moustakas, A. 2007. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim. Biophys. Acta. 1775, 21-62.
  15. Park, J., Leong, M. L., Buse, P., Maiyar, A. C., Firestone, G. L. and Hemmings, B. A. 1999. Serum and glucocorticoid- inducible kinase (SGK) is a target of the PI 3-kinase- stimulated signaling pathway. EMBO J. 18, 3024-3033. https://doi.org/10.1093/emboj/18.11.3024
  16. Perlman, R., Schiemann, W. P., Brooks, M. W., Lodish, H. F. and Weinberg, R. A. 2001. TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat. Cell Biol. 3, 708-714. https://doi.org/10.1038/35087019
  17. Rusai, K., Prokai, A., Szebeni, B., Fekete, A., Treszl, A., Vannay, A., Müller, V., Reusz, G., Heemann, U., Lutz, J., Tulassay, T. and Szabo, A. J. 2010. Role of serum and glucocorticoid- regulated kinase-1 in the protective effects of erythropoietin during renal ischemia/reperfusion injury. Biochem. Pharmacol. 79, 1173-1181. https://doi.org/10.1016/j.bcp.2009.11.022
  18. Saltzman, A., Munro, R., Searfoss, G., Franks, C., Jaye, M. and Ivashchenko, Y. 1998. Transforming growth factor-beta- mediated apoptosis in the Ramos B-lymphoma cell line is accompanied by caspase activation and Bcl-XL downregulation. Exp. Cell Res. 242, 244-254. https://doi.org/10.1006/excr.1998.4096
  19. Sanchez, A., Alvarez, A. M., Benito, M. and Fabregat, I. 1996. Apoptosis induced by transforming growth factor-beta in fetal hepatocytes primary cultures: involvement of reactive oxygen intermediates. J. Biol. Chem. 271, 7416-7422. https://doi.org/10.1074/jbc.271.13.7416
  20. Selvakumaran, M., Lin, H. K., Sjin, R. T., Reed, J. C., Liebermann, D. A. and Hoffman, B. 1994. The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor beta 1-induced apoptosis of myeloid leukemia cells. Mol. Cell Biol. 14, 2352-2360. https://doi.org/10.1128/MCB.14.4.2352
  21. Shi, Y. and Massague, J. 2003. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685-700. https://doi.org/10.1016/S0092-8674(03)00432-X
  22. Valderrama-Carvajal, H., Cocolakis, E., Lacerte, A., Lee, E. H., Krystal, G., Ali, S. and Lebrun, J. J. 2002. Activin/TGF-b induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP. Nat. Cell Biol. 4, 963-969. https://doi.org/10.1038/ncb885
  23. Won, M., Park, K. A., Byun, H. S., Kim, Y. R., Choi, B. L., Hong, J. H., Park, J., Seok, J. H., Lee, Y. H., Cho, C. H., Song, I. S., Kim, Y. K., Shen, H. M. and Hur, G. M. 2009. Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of REK2: Implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration. J. Hepatol. 51, 67-76. https://doi.org/10.1016/j.jhep.2009.02.027
  24. Yamamoto, M., Fukuda, K., Miura, N., Suzuki, R., Kido, T. and Komatsu, Y. 1998. Inhibition by dexamethasone of transforming growth factor beta1-induced apoptosis in rat hepatoma cells: a possible association with Bcl-xL induction. Hepatology 27, 959-966. https://doi.org/10.1002/hep.510270410
  25. Yoo, J., Ghiassi, M., Jirmanova, L., Balliet, A. G., Hoffman, B., Fornace Jr., A. J., Liebermann, D. A., Bottinger, E. P. and Roberts, A. B. 2003. Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J. Biol. Chem. 278, 43001-43007. https://doi.org/10.1074/jbc.M307869200
  26. Zhang, L., Cui, R., Cheng, X. and Du, J. 2005. Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating IkB kinase. Cancer Res. 65, 457-464.
  27. Zi, Z., Chapnick, D. A. and Liu, X. 2012. Dynamics of TGF-beta/Smad signaling. FEBS Lett. 586, 1921-1928. https://doi.org/10.1016/j.febslet.2012.03.063

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