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

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

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