Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

The Effect of Estrogen on the Transcription of the Insulin-like Growth Factor-I Gene in the Uterus

자궁 내 insulin-like growth factor-I 유전자 발현에 미치는 에스트로겐의 영향

  • 곽인석 (신라대학교 의생명과학대학 생물과학과)
  • Published : 2009.05.30
Download PDF
⟨ Previous Next ⟩

Abstract

The uterus plays a critical role in pregnancy and steroid hormones, and both estrogen (E2) and progesterone (P4) especially play important roles in the cross-talk between embryos and uterus to support the pregnancy. E2 stimulates uterine growth during early pregnancy to prepare for implantation of embryos. This cross-talk during the implantation period involves hormones (E2 and P4) and growth factors, including insulin-like growth factor-I (IGF-I). In the uterus of a pregnant pig, the action of E2 is mediated by estrogen receptor-${\beta}$ (ER-${\beta}$). The expression of ER-a was much higher in early pregnancy than in mid- and late- pregnancy, suggesting E2 secretion from embryos enhances transcription of ER-a during early pregnancy. In order to prove whether IGF-I is an E2 target gene, quantitative real-time PCR was performed on ovariectomized murine uterus with E2 and/or P4 treatment(s). Increased IGF-I mRNA expression was observed with E2 treatment, however, it was not significantly induced by P4 treatment, which clearly demonstrates that, in mice, E2 depends on the activation of uterine IGF-I gene expression. The expression of IGF-I in the uterus of pigs was much higher in early pregnancy than in mid- and late- pregnancy and these data exhibited the same expression pattern with the ER-${\beta}$ gene expression in the uterus. It suggests that a positive co-relationship between IGF-I and ER-${\beta}$ expression exists in the uterus, and that both gene expressions of IGF-I and ER-${\beta}$ are regulated by E2. It further suggests that uterine the IGF-I gene expression might be initiated by E2 secreted from embryos to increase ER-${\beta}$ gene expression, and that this increased ER-${\beta}$ further stimulates the expression of IGF-I in the uterus during early pregnancy.

자궁은 임신에 필수불가결한 기관으로, 에스트로겐(E2)과 프로게스테론(P4)은 태아와 자궁 사이의 상호 신호전달을 적절하게 조절하여, 임신을 확립하게 하는 필수적 요소이다. 임신 초기 E2는 배아의 안정적인 착상을 위하여 자궁의 성장을 촉진하는 역할을 담당한다. 이 시기 자궁에서 분비되는 인슐린유사 성장인자-I(IGF-I)와 E2/P4 간의 상호 신호전달이 임신 확립에 있어서 매우 중요한 역할을 한다. E2는 에스트로겐 수용체(ER)에 의해 그 작용이 결정되어지는데, 임신 돼지 자궁에서는 ER-${\alpha}$만이 발현됨을 증명하였다. 자궁에서 ER-${\alpha}$의 발현은 임신 중기나 말기보다 임신 초기 단계에서 높게 발현됨이 관찰되었다. 이는 배아에서 분비되는 E2가 ER-${\alpha}$의 발현을 증가시키는 역할을 함을 보여주는 결과이다. IGF-I이 E2 표적 유전자임을 증명하기 위하여 난소를 제거한 쥐에 E2/P4를 처리한 후 IGF-I의 발현을 측정한 결과, E2를 처리한 샘플에서는 IGF-I의 발현이 크게 증가하였으나, P4를 처리한 샘플에서는 큰 영향을 받지 않는 것으로 나타났다. 이 결과는 E2가 자궁에서 IGF-I의 발현을 증가시키는 역할을 수행함을 직접적으로 증명하였다. 임신한 돼지의 자궁에서 임신 시기별로 IGF-I 유전자의 발현을 조사한 결과 임신 초기에 가장 높은 발현을 보였고, 이 양상은 ER-${\alpha}$의 발현 형태와 아주 유사한 패턴을 나타내었다. 이는 임신 자궁에서 ER-${\alpha}$와 IGF-I의 발현이 상호 연관되어 있으며 ER-${\alpha}$와 IGF-I은 E2에 의해서 조절되어지는 유전자이며, 임신초기 배아에서 분비되는 E2가 자궁에서 ER-${\alpha}$의 발현을 증진시키고, 나아가서 이 ER-${\alpha}$가 자궁에서 IGF-I 유전자의 발현을 증가시키는 역할을 함을 보여주는 결과이다.

Keywords

References

  1. Bazer, F. W. and W. W. Thatcher. 1977. Theory of maternal recognition of pregnancy in swine based on estrogen controlled endocrine versus exocrine secretion of prostaglandin F2alpha by the uterine endometrium. Prostaglandins 14, 397-400 https://doi.org/10.1016/0090-6980(77)90185-X
  2. Chaudhuri, G. 2008. Nuclear receptors and female reproduction: a tale of 3 scientists, Jensen, Gustafsson, and O'Malley. Reprod. Sci. 15, 110-120 https://doi.org/10.1177/1933719108314516
  3. Choi, I., R. C. Simmen, and F. A. Simmen. 1996. Molecular cloning of cytochrome P450 aromatase complementary deoxyribonucleic acid from periimplantation porcine and equine blastocysts identifies multiple novel 5'-untranslated exons expressed in embryos, endometrium, and placenta. Endocrinology 137, 1457-67 https://doi.org/10.1210/en.137.4.1457
  4. Couse, J. F. and K. S. Korach. 1999. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr. Rev. 20, 358-417 https://doi.org/10.1210/er.20.3.358
  5. Hofig, A., F. J. Michel, F. A. Simmen, and R. C. Simmen. 1991. Constitutive expression of uterine receptors for insulin-like growth factor-I during the peri-implantation period in the pig. Biol. Reprod. 45, 533-539 https://doi.org/10.1095/biolreprod45.4.533
  6. Klotz, D. M., S. C. Hewitt, P. Ciana, M. Raviscioni, J. K. Lindzey, J. Foley, A. Maggi, R. P. DiAugustine, and K. S. Korach. 2002. Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk. J. Biol. Chem. 277, 8531-8537 https://doi.org/10.1074/jbc.M109592200
  7. Ko, Y., I. Choi, M. L. Green, F. A. Simmen, and R. C. Simmen. 1994. Transient expression of the cytochrome P450 aromatase gene in elongating porcine blastocysts is correlated with uterine insulin-like growth factor levels during peri-implantation development. Mol. Reprod. Dev. 37, 1-11 https://doi.org/10.1002/mrd.1080370102
  8. Korach, K. S., J. M. Emmen, V. R. Walker, S. C. Hewitt, M. Yates, J. M. Hall, D. L. Swope, J. C. Harrell, and J. F. Couse. 2003. Update on animal models developed for analyses of estrogen receptor biological activity. J. Steroid Biochem. Mol. Biol. 86, 387-391 https://doi.org/10.1016/S0960-0760(03)00348-0
  9. Krege, J. H., J. B. Hodgin, J. F. Couse, E. Enmark, M. Warner, J. F. Mahler, M. Sar, K. S. Korach, J. A. Gustafsson, and O. Smithies. 1998. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc. Natl. Acad. Sci. U S A 95, 15677-15682 https://doi.org/10.1073/pnas.95.26.15677
  10. Lee, K., J. Jeong, M. -J. Tsai, S. Tsai, J. P. Lydon, and F. J. DeMayo. 2006. Molecular mechanisms involved in progesterone receptor regulation of uterine function. J. Steroid Biochem. Mol. Biol. 102, 41-50 https://doi.org/10.1016/j.jsbmb.2006.09.006
  11. LeRoith, D. and C. T. Roberts, Jr. 1993. Insulin-like growth factors. Ann. N. Y. Acad. Sci. 692, 1-9 https://doi.org/10.1111/j.1749-6632.1993.tb26200.x
  12. Letcher, R., R. C. Simmen, F. W. Bazer, and F. A. Simmen. 1989. Insulin-like growth factor-I expression during early conceptus development in the pig. Biol. Reprod. 41, 1143-1151 https://doi.org/10.1095/biolreprod41.6.1143
  13. Liu, J. P., J. Baker, A. S. Perkins, E. J. Robertson, and A. Efstratiadis. 1993. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59-72
  14. McEwan, I. J. 2009. Nuclear receptors: one big family. Methods Mol. Bio. 505, 3-18 https://doi.org/10.1007/978-1-60327-575-0_1
  15. Paria, B. C., Y. M. Huet-Hudson, and S. K. Dey. 1993. Blastocyst's state of activity determines the 'window' of implantation in the receptive mouse uterus. Proc. Natl. Acad. Sci. U S A 90, 10159-10162 https://doi.org/10.1073/pnas.90.21.10159
  16. Reed, K., L. Badinga, D. L. Davis, T. E. Chung, and R. C. Simmen. 1996. Porcine endometrial glandular epithelial cells in vitro: transcriptional activities of the pregnancy-associated genes encoding antileukoproteinase and uteroferrin. Biol. Reprod. 55, 469-477 https://doi.org/10.1095/biolreprod55.2.469
  17. Simmen, F. A., R. C. Simmen, R. D. Geisert, F. Martinat-Botte, F. W. Bazer, and M. Terqui. 1992. Differential expression, during the estrous cycle and pre- and post-implantation conceptus development, of messenger ribonucleic acids encoding components of the pig uterine insulin-like growth factor system. Endocrinology 130, 1547-1556 https://doi.org/10.1210/en.130.3.1547
  18. Tsai, M. -J. and B. W. O'Malley. 1994. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annual Review of Biochemistry 63, 451-486 https://doi.org/10.1146/annurev.bi.63.070194.002315
  19. Weihua, Z., S. Andersson, G. Cheng, E. R. Simpson, M. Warner, and J. A. Gustafsson. 2003. Update on estrogen signaling. FEBS Lett. 546, 17-24 https://doi.org/10.1016/S0014-5793(03)00436-8