한국발생생물학회지:발생과생식 (Development and Reproduction)

  • 제17권2호
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  • Pages.99-109
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  • 2013
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  • 2465-9525(pISSN)
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  • 2465-9541(eISSN)
한국발생생물학회 (The Korean Society of Developmental Biology)
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Effect of Immortalization-Upregulated Protein-2 (IMUP-2) on Cell Death of Trophoblast

  • Jung, Ran (Department of Biomedical Science, CHA University) ;
  • Choi, Jong Ho (Department of Biomedical Science, CHA University) ;
  • Lee, Hyun Jung (Department of Biomedical Science, CHA University) ;
  • Kim, Jin Kyeoung (Department of Pharmacy, College of Pharmacy, CHA University) ;
  • Kim, Gi Jin (Department of Biomedical Science, CHA University)
  • 투고 : 2013.05.06
  • 심사 : 2013.05.22
  • 발행 : 2013.06.30
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초록

Trophoblasts, in the placenta, play a role for placental development as well as implantation in the early pregnancy. The characteristics and functions of trophoblast are identified by their localization and potency for proliferation, differentiation, and invasion. Thus, inadequate trophoblast cell death induces trophoblast dysfunction resulting in abnormal placental development and several gynecological diseases. Recently, it was reported that increased immortalization-upregulated protein-2 (IMUP-2) by hypoxia influences trophoblast apoptosis. However, IMUP-2 function on autophagy, which is type II programmed cell death remains unclear. In this study, we analyzed IMUP-2 expression in trophoblast cells (HTR8-SVneo) and compared IMUP-2 effects on cell death including apoptosis and autophagy in trophoblast regardless of IMUP-2 expression. Increased IMUP-2 in trophoblast by IMUP-2 gene transfection induces cell death, especially, apoptosis increases more than autophagy (p<0.05). However, the decreased IMUP-2 in trophoblasts after siRNA treatment decreased apoptosis with the decreased activities of caspase 3 and 7. The expressions of LC3 and MDC as an autophagosome makers and phosphorylated mTOR, which is a negative regulator for autophagy, increased. In addition, the S phase of cell cycle increased in trophoblasts when IMUP-2 expression decreased. Taken together, the alteration of IMUP-2 can control the balance between apoptosis and autophagy of trophoblasts resulting in functional involvement in placental development and in gynecological diseases by regulating the function of trophoblasts.

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참고문헌

  1. Bildirici I, Longtine MS, Chen B, Nelson DM (2012) Survival by self-destruction: a role for autophagy in the placenta? Placenta 33:591-598. https://doi.org/10.1016/j.placenta.2012.04.011
  2. De Falco M, De Luca L, Acanfora F, Cavallotti I, Cottone G, Laforgia V, De Luca B, Baldi A, De Luca A (2001) Alteration of the Bcl-2:Bax ratio in the placenta as pregnancy proceeds. Histochem J 33:421-425. https://doi.org/10.1023/A:1013728012048
  3. Hughes M, Dobric N, Scott IC, Su L, Starovic M, St-Pierre B, Egan SE, Kingdom JC, Cross JC (2004) The Hand1, Stra13 and Gcm1 transcription factors override FGF signaling to promote terminal differentiation of trophoblast stem cells. Dev Biol 271:26-37. https://doi.org/10.1016/j.ydbio.2004.03.029
  4. Huppertz B (2008) The anatomy of the normal placenta. J Clin Pathol 61:1296-1302. https://doi.org/10.1136/jcp.2008.055277
  5. Huppertz B, Frank HG, Kingdom JC, Reister F, Kaufmann P (1998) Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol 110:495-508. https://doi.org/10.1007/s004180050311
  6. Huppertz B, Frank HG, Reister F, Kingdom J, Korr H, Kaufmann P (1999) Apoptosis cascade progresses during turnover of human trophoblast: analysis of villous cytotrophoblast and syncytial fragments in vitro. Lab Invest 79:1687-1702.
  7. Huppertz B, Kadyrov M, Kingdom JC (2006) Apoptosis and its role in the trophoblast. Am J Obstet Gynecol 195:29-39. https://doi.org/10.1016/j.ajog.2005.07.039
  8. Jeon SY, Lee HJ, Park JM, Jung HM, Yoo JK, Lee HJ, Lee JS, Cha DH, Kim JK, Kim GJ (2010) Increased immortalization-upregulated protein 2 (IMUP-2) by hypoxia induces apoptosis of the trophoblast and pre-eclampsia. J Cell Biochem 110:522-530.
  9. Kim JK, An HJ, Kim NK, Ahn JY, Kim KS, Kang YJ, Ko JJ, Oh D, Lee C, Kim SJ, Cha KY (2003) IMUP-1 and IMUP-2 genes are up-regulated in human ovarian epithelial tumors. Anticancer Res 23:4709-4713.
  10. Kim JK, Ryll R, Ishizuka Y, Kato S (2000) Identification of cDNAs encoding two novel nuclear proteins, IMUP-1 and IMUP-2, upregulated in SV40-immortalized human fibroblasts. Gene 257:327-334. https://doi.org/10.1016/S0378-1119(00)00414-5
  11. Kim SH, Banga S, Jha KK, Ozer HL (1998) SV40- mediated transformation and immortalization of human cells. Dev Biol Stand 94:297-302.
  12. Kim SJ, An HJ, Kim HJ, Jungs HM, Lee S, Ko JJ, Kim IH, Sakuragi N, Kim JK (2008) Imup-1 and imup-2 overexpression in endometrial carcinoma in Korean and Japanese populations. Anticancer Res 28: 865-871.
  13. LeBrun DP, Warnke RA, Cleary ML (1993) Expression of bcl-2 in fetal tissues suggests a role in morphogenesis. Am J Pathol 142:743-753.
  14. Lockshin RA, Zakeri Z (2004) Apoptosis, autophagy, and more. Int J Biochem Cell Biol 36(12):2405- 2419. https://doi.org/10.1016/j.biocel.2004.04.011
  15. Na KH, Lee HJ, Jung J, Kim GJ (2010) Expression of norepinephrine transporter in pre-eclamptic placenta. Dev Reprod 14:65-74.
  16. Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14:381-395. https://doi.org/10.1016/S0898-6568(01)00271-6
  17. Oh SY, Choi SJ, Kim KH, Cho EY, Kim JH, Roh CR (2008) Autophagy-related proteins, LC3 and Beclin-1, in placentas from pregnancies complicated by preeclampsia. Reprod Sci 15:912-920. https://doi.org/10.1177/1933719108319159
  18. Ozer HL (2000) SV40-mediated immortalization. Prog Mol Subcell Biol 24:121-153.
  19. Ray J, Jurisicova A, Caniggia I (2009) IFPA Trophoblast Research Award Lecture: the dynamic role of Bcl-2 family members in trophoblast cell fate. Placenta 30 Suppl A:S96-100.
  20. Ray JE, Garcia J, Jurisicova A, Caniggia I (2010) Mtd/ Bok takes a swing: proapoptotic Mtd/Bok regulates trophoblast cell proliferation during human placental development and in preeclampsia. Cell Death Differ 17:846-859. https://doi.org/10.1038/cdd.2009.167
  21. Roos S, Lagerlof O, Wennergren M, Powell TL, Jansson T (2009) Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mTOR signaling. Am J Physiol Cell Physiol 297:C723-731. https://doi.org/10.1152/ajpcell.00191.2009
  22. Ryoo ZY, Jung BK, Lee SR, Kim MO, Kim SH, Kim HJ, Ahn JY, Lee TH, Cho YH, Park JH, Kim JK (2006) Neoplastic transformation and tumorigenesis associated with overexpression of IMUP-1 and IMUP-2 genes in cultured NIH/3T3 mouse fibroblasts. Biochem Biophys Res Commun 349:995-1002. https://doi.org/10.1016/j.bbrc.2006.08.137
  23. Scifres CM, Nelson DM (2009) Intrauterine growth restriction, human placental development and trophoblast cell death. J Physiol 587:3453-3458. https://doi.org/10.1113/jphysiol.2009.173252
  24. Singh R (2011) Hypothalamic lipophagy and energetic balance. Aging (Albany NY) 3:934-942.
  25. Smith SC, Baker PN, Symonds EM (1997a) Increased placental apoptosis in intrauterine growth restriction. Am J Obstet Gynecol 177:1395-1401. https://doi.org/10.1016/S0002-9378(97)70081-4
  26. Smith SC, Baker PN, Symonds EM (1997b) Placental apoptosis in normal human pregnancy. Am J Obstet Gynecol 177:57-65. https://doi.org/10.1016/S0002-9378(97)70438-1
  27. Tamura M, Sawabata N, Kobayashi S, Umezu H, Seki N, Yoshii N, Karube Y, Araki O, Ishihama H, Nagai S, Miyoshi S (2007) Prognostic significance of p21 protein expression in patients with pulmonary squamous cell carcinoma following induction chemotherapy. Ann Thorac Cardiovasc Surg 13:9-14.
  28. Tomas SZ, Prusac IK, Roje D, Tadin I (2011) Trophoblast apoptosis in placentas from pregnancies complicated by preeclampsia. Gynecol Obstet Invest 71:250-255. https://doi.org/10.1159/000320289