Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)
Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)
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DOI：
10.1038/onc.2010.541
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发表时间：
2011-04-01
期刊：
影响因子：
8
通讯作者：
Bae, J.
中科院分区：
文献类型：
--
作者：
Kim, J-H;Yoon, S.;Bae, J.
FOXL2基因的一些突变导致卵巢早衰，并伴有眼睑肥大、上睑下垂、内翻综合征I型疾病，FOXL2基因缺失的小鼠出现颗粒细胞发育缺陷。最近，在大多数成人型卵巢颗粒细胞瘤(GCTS)中发现了FOXL2 c.402C>；G，这是一种导致P.C134W改变的新的体细胞突变。在本研究中，我们探讨了C134W突变在GCTS发病中的可能机制。野生型(WT)和突变型FOXL2表现出不同的凋亡活性。具体来说，WT FOXL2诱导了显著的颗粒细胞死亡，但突变体的细胞死亡最少。FOXL2诱导的凋亡反应在很大程度上依赖于caspase8、Bid和BAK，因为这三种蛋白中的任何一种的缺失都会抑制FOXL2引发完整的凋亡反应。Caspase8的激活、BAK的寡聚和细胞色素c的释放均与WT FOXL2表达诱导的细胞凋亡有关。相比之下，突变的FOXL2不能引发完整的凋亡信号反应。此外，我们还发现突变体和野生型细胞中肿瘤坏死因子受体1和Fas(CD95/APO-1)的表达上调不同，而肿瘤坏死因子受体1或Fas的沉默和由肿瘤坏死因子受体1或Fas介导的死亡信号的阻断分别以肿瘤坏死因子受体1和Fas的形式存在，导致FOXL2诱导的细胞凋亡显著减弱。此外，表达WT FOXL2或突变体的颗粒细胞对死亡受体的激活和血清的剥夺表现出明显的细胞死亡敏感性。因此，FOXL2及其突变体的活性差异可能是GCT发生的部分原因。Oncogene(2011)30,1653-1663；doi：10.1038/onc.2010.541；2010年11月29日在线发布
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 greatly dependent on caspase 8, BID and BAK because the depletion of any of these three proteins inhibited FOXL2 from eliciting the full apoptotic response. Activation of caspase 8 and subsequent increased production of truncated BID, and oligomerization of BAK, and release of cytochrome c were all associated with the apoptosis induced by WT FOXL2 expression. In 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. Oncogene (2011) 30, 1653-1663; doi:10.1038/onc.2010.541; published online 29 November 2010