Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis.
Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis.
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DOI：
10.1083/jcb.201111063
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发表时间：
2012-07-09
期刊：
影响因子：
--
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Qi Y;Tian X;Liu J;Han Y;Graham AM;Simon MC;Penninger JM;Carmeliet P;Li S
上皮管腔形成过程中的细胞凋亡由缺氧诱导的促凋亡蛋白Bnip 3的表达介导，而Bnip 3的表达由AIF介导的活性氧产生和HIF-2α稳定化促进。细胞凋亡是胚胎上皮细胞形态发生过程中的一个重要环节，但其机制尚不清楚。在本文中，我们使用胚胎干细胞分化的胚状体（EBs）作为一个模型，发现Bnip 3（Bcl-2/腺病毒E1 B 19-kD相互作用蛋白），一个只有BH 3的促凋亡蛋白，在空化过程中以缺氧依赖的方式高度上调。短发夹RNA沉默Bnip 3抑制核心细胞的凋亡和延迟空化。我们发现Bnip 3的上调主要是由缺氧诱导因子（HIF）-2介导的。阻断HIF-1和HIF-2的共同β亚基HIF-2α或HIF-1β可抑制Bnip 3的上调，抑制细胞凋亡和空泡形成。我们进一步表明，凋亡诱导因子（AIF）与Bnip 3合作，以促进管腔清除。Bnip 3沉默AIF无效EB几乎阻断细胞凋亡和空化。此外，AIF还通过线粒体产生活性氧和随后的HIF-2α稳定来调节Bnip 3的表达。这些结果揭示了通过HIF、Bnip 3和AIF介导的缺氧诱导的核心细胞凋亡的空化机制。
Apoptosis during epithelial lumen formation is mediated by hypoxia-induced expression of the proapoptotic protein Bnip3, which is promoted by AIF-mediated reactive oxygen species production and HIF-2α stabilization. Apoptosis is an essential step in cavitation during embryonic epithelial morphogenesis, but its mechanisms are largely unknown. In this paper, we used embryonic stem cell–differentiated embryoid bodies (EBs) as a model and found that Bnip3 (Bcl-2/adenovirus E1B 19-kD interacting protein), a BH3-only proapoptotic protein, was highly up-regulated during cavitation in a hypoxia-dependent manner. Short hairpin RNA silencing of Bnip3 inhibited apoptosis of the core cells and delayed cavitation. We show that the Bnip3 up-regulation was mediated mainly by hypoxia-inducible factor (HIF)–2. Ablation of HIF-2α or HIF-1β, the common β subunit of HIF-1 and -2, suppressed Bnip3 up-regulation and inhibited apoptosis and cavitation. We further show that apoptosis-inducing factor (AIF) cooperated with Bnip3 to promote lumen clearance. Bnip3 silencing in AIF-null EBs nearly blocked apoptosis and cavitation. Moreover, AIF also regulated Bnip3 expression through mitochondrial production of reactive oxygen species and consequent HIF-2α stabilization. These results uncover a mechanism of cavitation through hypoxia-induced apoptosis of the core cells mediated by HIFs, Bnip3, and AIF.
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影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
64.8
作者：
Joza, N;Susin, SA;Penninger, JM
通讯作者：
Penninger, JM
DOI：
10.1073/pnas.0603950103
发表时间：
2006-06-27
影响因子：
11.1
作者：
Brown, Doris;Yu, Benjamin D.;Martin, Gail R.
通讯作者：
Martin, Gail R.
影响因子：
4.8
作者：
Lee, M;Hwang, JT;Ha, JH
通讯作者：
Ha, JH
DOI：
10.1083/jcb.200203073
发表时间：
2002-06-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Li S;Harrison D;Carbonetto S;Fassler R;Smyth N;Edgar D;Yurchenco PD
通讯作者：
Yurchenco PD