ABSTRACT Some mutations in _FOXL2_ result in premature ovarian failure accompanied by blepharophimosis, ptosis, epicanthus inversus syndrome type I disease, and FOXL2-null mice exhibit

developmental defects in granulosa cells. Recently, _FOXL2_ c.402C>G, a new somatic mutation that leads to a p.C134W change, was found in the majority of adult-type ovarian granulosa cell

tumors (GCTs). In this study, we investigated the possible mechanisms by which the C134W mutation contributes to the development of GCTs. Wild-type (WT) and mutant FOXL2 displayed

differential apoptotic activities. Specifically, WT FOXL2 induced significant granulosa cell death, but the mutant exhibited minimal cell death. The FOXL2-induced apoptotic response was

contrast, the mutant FOXL2 was unable to elicit the full array of apoptotic signaling responses. In addition, we found differential TNF-R1 (tumor necrosis factor-receptor 1) and Fas

(CD95/APO-1) upregulation between the WT and the mutant, and the silencing of TNF-R1 or Fas and the blockage of the death signaling mediated by TNF-R1 or Fas using TNF-Fc or Fas-Fc,

respectively, resulted in significant attenuations of FOXL2-induced apoptosis. Moreover, granulosa cells that expressed either WT FOXL2 or mutant exhibited distinct cell death sensitivities

on activation of death receptors and deprivation of serum. Thus, the differential activities of FOXL2 and its mutant may partially account for the pathophysiology of GCT development. Access

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procaspase-9. _J Biol Chem_ 274: 11549–11556. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by the Basic Science Research Program

(2009-0066320) and the Priority Research Centers Program (2009-0093821) through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology and by a

grant (A084923) from the Korea Healthcare Technology R&D Project from the Ministry of Health, Welfare and Family Affairs. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Biomedical Science, College of Life Science, CHA University, Seongnam, Korea J-H Kim, S Yoon, M Park, H-O Park, J-J Ko & J Bae * Department of Life Science, Chung-Ang University, Seoul,

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COMPETING INTERESTS The authors declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Kim, JH., Yoon, S., Park, M. _et al._

Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W). _Oncogene_ 30, 1653–1663 (2011).

https://doi.org/10.1038/onc.2010.541 Download citation * Received: 14 April 2010 * Revised: 28 September 2010 * Accepted: 18 October 2010 * Published: 29 November 2010 * Issue Date: 07 April

2011 * DOI: https://doi.org/10.1038/onc.2010.541 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is

not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * FOXL2 * granulosa cell tumor * apoptosis * caspase

* BAK * death receptors