Development and Reproduction (한국발생생물학회지:발생과생식)

The Korean Society of Developmental Biology (한국발생생물학회)
권호 표지

Differential Activities of FOXL2 and Its Mutants on SF-1-Induced CYP19 Transcriptional Activation

SF-1을 매개한 CYP19의 전사활성에 미치는 FOXL2 야생형과 돌연변이형의 차별적 영향

  • Park, Mi-Ra (Dept. of Biomedical Science, College of Life Science, CHA University) ;
  • Kim, Ah-Young (Dept. of Biomedical Science, College of Life Science, CHA University) ;
  • Na, Soon-Young (Dept. of Biomedical Science, College of Life Science, CHA University) ;
  • Kim, Hong-Man (Dept. of Life Science, Chung-Ang University) ;
  • Lee, Kang-Seok (Dept. of Life Science, Chung-Ang University) ;
  • Bae, Jee-Hyeon (Dept. of Biomedical Science, College of Life Science, CHA University) ;
  • Ko, Jeong-Jae (Dept. of Biomedical Science, College of Life Science, CHA University)
  • 박미라 (CHA 의과학대학교 의생명대학 의생명과학과) ;
  • 김아영 (CHA 의과학대학교 의생명대학 의생명과학과) ;
  • 나순영 (CHA 의과학대학교 의생명대학 의생명과학과) ;
  • 김홍만 (중앙대학교 자연과학대학 생명과학과) ;
  • 이강석 (중앙대학교 자연과학대학 생명과학과) ;
  • 배지현 (CHA 의과학대학교 의생명대학 의생명과학과) ;
  • 고정재 (CHA 의과학대학교 의생명대학 의생명과학과)
  • Received : 2010.03.09
  • Accepted : 2010.04.29
  • Published : 2010.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

FOXL2 is a winged-helix/forkhead (FH) domain transcription factor, and mutations in FOXL2 gene are responsible for blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). BPES is an autosomal dominant genetic disease. BPES type I patients exhibit both premature ovarian failure (POF) and eyelid malformation, while only the eyelid defect is observed in BPES type II. FOXL2-null ovaries showed a blockage of granulosa cell differentiation, suggesting that FOXL2 plays an essential role for proper ovarian folliculogenesis. Previously, we screened for FOXL2-interacting proteins and identified steroidogenic factor-1 (SF-1) which is known to be required for gonad development and transactivates steroidogenic enzymes including CYP19. In the present study, we demonstrated that FOXL2 transactivates CYP19 and stimulated the transcriptional activation of CYP19 induced by SF-1. In contrast, FOXL2 mutants found in BPES type I and II exhibited compromised abilities to enhance CYP19 induction mediated by SF-1. Thus, this study provides a functional difference between wild-type FOXL2 and its mutants which may aid to understand pathophysiology of BPES elicited by FOXL2 mutations.

FOXL2는 winged-helix/forkhead(FH) 도메인 전사인자로서 FOXL2 유전자에 돌연변이가 발생할 경우 blepharophimosis-ptosis-epicanthus inversus syndrome이라 불리는 BPES 질병이 유발되게 된다. BPES는 상염색체 우성인 유전적 질환이다. BPES type I의 환자는 조기난소부전증(POF)과 안검하수 증상이 함께 나타나는 반면, BPES type II의 경우 안검하수 및 소안검 등 안면기형만이 유발된다. FOXL2 단백질이 결여된 난소에서 granulosa 세포의 분화가 멈추는 것으로 보아 FOXL2가 정상적인 난소의 folliculogenesis에 필수적인 역할을 하고 있음을 시사한다. 이전의 연구 결과에서, 본 연구진은 FOXL2와 상호작용하는 단백질에 대한 스크리닝을 통해 스테로이드 합성효소인 CYP19 전사활성에 영향을 미치는 steroidogenic factor-1(SF-1)을 동정하였다. 이번 연구를 통해 FOXL2가 CYP19의 전사를 향상시키고, SF-1에 의한 CYP19의 전사를 더욱 촉진시킨다는 것을 증명하였다. 이와 반대로, BPES 타입 I과 II에서 발견된 FOXL2의 돌연변이형들은 SF-1에 의해 증가된 CYP19의 전사활성을 향상시키는 능력이 감소함을 보여주었다. 본 실험을 통해 FOXL2 돌연변이에 의해 유발되어지는 BPES 질환의 병리생리학적인 이해에 대해 도움을 줄 수 있는 FOXL2의 야생형과 돌연변이형 사이의 서로 다른 기능적인 차이점을 규명하였다.

Keywords

References

  1. Beysen D, Vandesompele J, Messiaen L, De Paepe A, De Baere E (2004) The human FOXL2 mutation database. Hum Mutat 24:189-193. https://doi.org/10.1002/humu.20079
  2. Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G (2001) The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159-166. https://doi.org/10.1038/84781
  3. Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, Pannetier M, De Baere E, Messiaen L, Cotinot C, Fellous M, Veitia RA (2002) Evolution and expression of FOXL2. J Med Genet 39:916-922. https://doi.org/10.1136/jmg.39.12.916
  4. De Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, De Sutter P, Devriendt K, Dixon M, Fellous M, Fryns JP, Garza A, Jonsrud C, Koivisto PA, Krause A, Leroy BP, Meire F, Plomp A, Van Maldergem L, De Paepe A, Veitia R, Messiaen L (2003) FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. Am J Hum Genet 72:478-487. https://doi.org/10.1086/346118
  5. de Moraes-Ruehsen M, Jones GS (1967) Premature ovarian failure. Fertil Steril 18:440-461. https://doi.org/10.1016/S0015-0282(16)36362-2
  6. Falender AE, Lanz R, Malenfant D, Belanger L, Richards JS (2003) Differential expression of steroidogenic factor-1 and FTF/LRH-1 in the rodent ovary. Endocrinology 144:3598-3610. https://doi.org/10.1210/en.2002-0137
  7. Gurates B, Amsterdam A, Tamura M, Yang S, Zhou J, Fang Z, Amin S, Sebastian S, Bulun SE (2003) WT1 and DAX-1 regulate SF-1-mediated human P450arom gene expression in gonadal cells. Mol Cell Endocrinol 208:61-75. https://doi.org/10.1016/S0303-7207(03)00198-9
  8. Hanley NA, Rainey WE, Wilson DI, Ball SG, Parker KL (2001) Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: Potential interactions in gene regulation. Mol Endocrinol 15:57-68. https://doi.org/10.1210/me.15.1.57
  9. Hoek A, Schoemaker J, Drexhage HA (1997) Premature ovarian failure and ovarian autoimmunity. Endocr Rev 18:107-134. https://doi.org/10.1210/er.18.1.107
  10. Jagarlamudi K, Liu L, Adhikari D, Reddy P, Idahl A, Ottander U, Lundin E, Liu K (2009) Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation. PLoS One 4:e6186. https://doi.org/10.1371/journal.pone.0006186
  11. Jeyasuria P, Ikeda Y, Jamin SP, Zhao L, De Rooij DG, Themmen AP, Behringer RR, Parker KL (2004) Cellspecific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Mol Endocrinol 18: 1610-1619. https://doi.org/10.1210/me.2003-0404
  12. Leers-Sucheta S, Morohashi K, Mason JI, Melner MH (1997) Synergistic activation of the human type II 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase promoter by the transcription factor steroidogenic factor-1/adrenal 4-binding protein and phorbol ester. J Biol Chem 272:7960-7967. https://doi.org/10.1074/jbc.272.12.7960
  13. Luo X, Ikeda Y, Parker KL (1994) A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481-490. https://doi.org/10.1016/0092-8674(94)90211-9
  14. Matzuk MM, Lamb DJ (2002) Genetic dissection of mammalian fertility pathways. Nat Cell Biol Suppl:s41-49.
  15. Michael MD, Kilgore MW, Morohashi K, Simpson ER (1995) Ad4BP/SF-1 regulates cyclic AMP-induced transcription from the proximal promoter (PII) of the human aromatase P450 (CYP19) gene in the ovary. J Biol Chem 270:13561-13566. https://doi.org/10.1074/jbc.270.22.13561
  16. Pannetier M, Fabre S, Batista F, Kocer A, Renault L, Jolivet G, Mandon-Pepin B, Cotinot C, Veitia R, Pailhoux E (2006) FOXL2 activates P450 aromatase gene transcription: towards abetter characterization of the early steps of mammalian ovarian development. J Mol Endocrinol 36:399-413. https://doi.org/10.1677/jme.1.01947
  17. Park M, Shin E, Won M, Kim JH, Go H, Kim HL, Ko JJ, Lee K, Bae J (2010) FOXL2 interacts with steroidogenic factor-1 (SF-1) and represses SF-1-induced CYP-17 transcription in granulosa cells. Mol Endocrinol 24:1024-1036. https://doi.org/10.1210/me.2009-0375
  18. Parker KL, Rice DA, Lala DS, Ikeda Y, Luo X, Wong M, Bakke M, Zhao L, Frigeri C, Hanley NA, Stallings N, Schimmer BP (2002) Steroidogenic factor 1: An essential mediator of endocrine development. Recent Prog Horm Res 57:19-36. https://doi.org/10.1210/rp.57.1.19
  19. Pisarska MD, Bae J, Klein C, Hsueh AJ (2004) Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology 145:3424-3433. https://doi.org/10.1210/en.2003-1141
  20. Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC, Treier M (2004) The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131:933-942. https://doi.org/10.1242/dev.00969
  21. Shapiro DB, Pappalardo A, White BA, Peluso JJ (1996) Steroidogenic factor-1 as a positive regulator of rat granulosa cell differentiation and a negative regulator of mitosis. Endocrinology 137:1187-1195. https://doi.org/10.1210/en.137.4.1187
  22. Simpson JL (2008) Genetic and phenotypic heterogeneity in ovarian failure: Overview of selected candidate genes. Ann N Y Acad Sci 1135:146-154. https://doi.org/10.1196/annals.1429.019
  23. Sugawara T, Holt JA, Kiriakidou M, Strauss JF 3rd (1996) Steroidogenic factor 1-dependent promoter activity of the human steroidogenic acute regulatory protein (St-AR) gene. Biochemistry 35:9052-9059. https://doi.org/10.1021/bi960057r
  24. Uda M, Ottolenghi C, Crisponi L, Garcia JE, Deiana M, Kimber W, Forabosco A, Cao A, Schlessinger D, Pilia G (2004) Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum Mol Genet 13:1171-1181. https://doi.org/10.1093/hmg/ddh124
  25. Uhlenhaut NH, Treier M (2006) Foxl2 function in ovarian development. Mol Genet Metab 88:225-234. https://doi.org/10.1016/j.ymgme.2006.03.005
  26. Zhou LY, Wang DS, Shibata Y, Paul-Prasanth B, Suzuki A, Nagahama Y (2007) Characterization, expression and transcriptional regulation of P450c17-I and -II in the medaka, Oryzias latipes. Biochem Biophys Res Commun 362:619-625. https://doi.org/10.1016/j.bbrc.2007.08.044
  27. 김정욱, 염혜원, 이형송, 송견지, 천강우, 박용석, 김계현 (2000) 조기 난소 부전증(Premature Ovarian Failure, POF) 환자에서 난포 자극 호르몬 수용체 유전자 변이 및 발현 양상에 대한 분석. 발생과 생식 4:61-66.