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난소암 세포에서 IEX-1과 MCL-1 단백질들의 세포사멸 기능에 관한 상호작용
윤성민,나순영,이강석,배지현,김홍만 한국발생생물학회 2010 발생과 생식 Vol.14 No.2
Apoptosis is a crucial mechanism for the proper regulation of homeostasis. BCL-2 family proteins are key molecules which control cellular survival and apoptosis. MCL-1(myeloid cell leukemia-1) is a pro-survival member of BCL- 2 family that promotes the survival of cells, and is highly expressed in diverse cancers including ovarian cancer, leukemia, and cervical cancer. Previously we identified IEX-1(immediate early response gene X-1) as a binding partner of MCL- 1. In the present study, we demonstrated that overexpression of IEX-1 induces apoptosis of ovarian cancer cells. Moreover, IEX-1 significantly attenuated the pro-survival function of MCL-1 in these cells. Also, IEX-1-induced cell death activity was able to be modulated by changes in the expression level of MCL-1. Thus, these results suggest that both IEX-1 and MCL-1 modulate each other’s function controlling cellular survival and death and the inhibitory activity of IEX-1 toward MCL-1 may be applied for the development of chemotherapeutics.
SF-1을 매개한 CYP19의 전사활성에 미치는 FOXL2 야생형과 돌연변이형의 차별적 영향
박미라,고정재,김아영,나순영,이강석,배지현,김홍만 한국발생생물학회 2010 발생과 생식 Vol.14 No.2
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.
Hepatocyte toll-like receptor 4 mediates lipopolysaccharide-induced hepcidin expression
이용수,김용훈,정윤석,김기선,김돈규,나순영,이지민,이철호,최흥식 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-
Hepcidin expression is induced by inflammatory molecules such as lipopolysaccharide (LPS) via a macrophage-mediated pathway. Although hepatocytes directly respond to LPS, the molecular mechanism underlying toll-like receptor (TLR)-dependent hepcidin expression by hepatocytes is mostly unknown. Here we show that LPS can directly induce the mRNA expression and secretion of hepcidin by hepatocytes via TLR4 activation. Using hepatocytes deficient in TLR4, myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor inducing interferon-β (TRIF), we demonstrated that LPS-induced hepcidin expression by hepatocytes is regulated by its specific receptor, TLR4, via a MyD88-dependent signaling pathway. Hepcidin promoter activity was significantly increased by MyD88-dependent downstream signaling molecules (interleukin-1 receptorassociated kinase (IRAK) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which activate c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1). We then confirmed that LPS stimulation induced the phosphorylation of JNK and c-Jun, and observed strong occupancy of the hepcidin promoter by c-Jun. Promoter mutation analysis also identified the AP-1-binding site on the hepcidin promoter. Finally, bone marrow transplantation between wild-type and TLR4 knockout mice revealed that hepatic TLR4-dependent hepcidin expression was comparable to macrophage TLR4-dependent hepcidin expression induced by LPS. Taken together, these results suggest that TLR4 expressed by hepatocytes regulates hepcidin expression via the IRAK– TRAF6–JNK–AP-1 axis.