The androgen receptor mediates antiapoptotic function in myometrial cells.
The androgen receptor mediates antiapoptotic function in myometrial cells.
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DOI：
10.1038/cddis.2014.303
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发表时间：
2014-07-17
影响因子：
9
通讯作者：
Dong, X.
中科院分区：
文献类型：
--
作者：
Li, H.;Li, Y.;Morin, D.;Plymate, S.;Lye, S.;Dong, X.
在怀孕期间，子宫肌层表型被编程为三个特征阶段，即早期增殖期、中期肥厚期和晚期收缩期。妊娠早期和中期子宫肌层生长加快涉及细胞增殖、抗凋亡和分化的复杂过程。我们之前已经证明，雄激素受体 (AR) 通过在妊娠早期调节 IGF-1 信号传导是子宫肌层细胞增殖所必需的。在此，我们报道 AR 还在人类子宫肌细胞中发挥其抗凋亡功能。增强的 AR 表达可以起到保护作用，而 AR 沉默则可以使子宫肌层细胞对内在和外在的凋亡刺激变得敏感。 AR 激动剂抑制，而 AR 拮抗剂诱导子宫肌细胞发生凋亡细胞死亡。基因微阵列分析证实，AR在子宫肌细胞中的核心功能是通过涉及表皮生长因子（EGF）信号传导、RNA剪接和DNA修复过程的三个主要基因组来调节细胞周期和细胞凋亡。 AR 通过两种不同的途径介导其抗凋亡功能。在受体依赖性通路中，AR 是 EGF 信号通路内多种蛋白因子表达所必需的。 AR 通过 PI3K/Akt 通路增强抗凋亡蛋白 Mcl-1 的表达。在配体依赖性途径中，AR 激动剂触发 Src 激酶的激活，进而磷酸化 STAT3 以增加 Mcl-1 的表达。我们从这些结果得出结论，AR 信号在子宫肌层细胞中发挥抗凋亡功能，进一步支持其在子宫肌层表型编程中的关键作用。
During pregnancy, myometrial phenotype is programmed into three characteristic stages referred to as the early proliferative, the midterm hypertrophic, and the late contractile stage. Increased myometrial growth in the early and midterm of pregnancy involves a complex process of cell proliferation, antiapoptosis and differentiation. We have previously demonstrated that the androgen receptor (AR) is required for myometrial cell proliferation by modulating IGF-1 signaling during early pregnancy. Here, we report that AR also exerts its antiapoptotic function in human myometrial cells. Enhanced AR expression protects, whereas AR silencing sensitizes myometrial cells to both intrinsic and extrinsic apoptotic stimuli. AR agonist inhibits, whereas AR antagonist induces myometrial cells to undergo apoptotic cell death. Gene microarray analysis confirms that the central functions of AR in myometrial cells are to regulate cell cycling and apoptosis through three major gene groups involving the epidermal growth factor (EGF) signaling, RNA splicing and DNA repair processes. AR mediates its antiapoptotic function through two distinct pathways. In the receptor-dependent pathway, AR is required for the expression of several protein factors within the EGF signaling pathway. Through the PI3K/Akt pathway, AR enhances the expression of the antiapoptotic protein Mcl-1. In the ligand-dependent pathway, AR agonist triggers the activation of Src kinase, which in turn phosphorylates STAT3 to increase Mcl-1 expression. We conclude from these results that the AR signaling exerts antiapoptotic function in myometrial cells, further supporting its key role in programming of myometrial phenotype.
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影响因子：
--
作者：
Cohen NA;Stewart ML;Gavathiotis E;Tepper JL;Bruekner SR;Koss B;Opferman JT;Walensky LD
通讯作者：
Walensky LD
影响因子：
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通讯作者：
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通讯作者：
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作者：
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作者：
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