Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro
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DOI：
10.1073/pnas.0400443101
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发表时间：
2004-03-09
影响因子：
11.1
通讯作者：
Brugge, JS
中科院分区：
文献类型：
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作者：
Mills, KR;Reginato, M;Brugge, JS
在组织发育过程中，调节细胞消除以产生中空腔的分子事件知之甚少。通过使用MCF-10A人乳腺上皮细胞形成中空腺泡样结构的体外形态发生模型，我们观察到了与管腔形成过程中丢失的细胞相关的半胱天冬酶介导的凋亡和自噬。在这里，我们表明，肿瘤坏死因子相关凋亡诱导配体（TRAIL）介导的诱导与管腔形成相关的自噬过程。TRAIL在3D基底膜培养物中MCF-10A乳腺上皮细胞的形态发生期间上调，并且在形态发生期间抑制TRAIL信号传导阻断自噬空泡的形成。此外，用外源性TRAIL处理在单层和3D培养物中诱导广泛的自噬。当与半胱天冬酶3活性的抑制（通过Bcl-X-L过表达）组合时，抑制TRAIL诱导的自噬导致管腔填充。因此，TRAIL调节腺泡形态发生期间的自噬程序，其与半胱天冬酶介导的凋亡事件一起导致MCF-10A形态发生期间的管腔形成。
The molecular events regulating the elimination of cells to create a hollow lumen during tissue development are poorly understood. By using an in vitro morphogenesis model in which MCF-10A human mammary epithelial cells form hollow acini-like structures, we have observed both caspase-mediated apoptosis and autophagy associated with cells that are lost during lumen formation. Here, we show that the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates induction of autophagic processes associated with lumen formation. TRAIL is up-regulated during morphogenesis of MCF-10A mammary epithelial cells in 3D basement-membrane cultures and inhibition of TRAIL signaling during morphogenesis blocks the formation of autophagic vacuoles. In addition, treatment with exogenous TRAIL induces extensive autophagy in monolayer and 3D cultures. When combined with inhibition of caspase 3 activity (by Bcl-X-L overexpression), inhibition of TRAIL-induced autophagy results in luminal filling. Thus, TRAIL regulates an autophagic program during acinar morphogenesis, which together with caspase-mediated apoptotic events, results in lumen formation during MCF-10A morphogenesis.