FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas.
FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas.
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FOXO3A（叉子盒O3A）缺乏保护特发性肺纤维化（IPF）成纤维细胞免受I型聚合胶原基质诱导的胶原蛋白基质诱导的凋亡，可通过Caveolin-1（CAV-1）和FAS诱导。
DOI：
10.1371/journal.pone.0061017
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Henke CA
中科院分区：
文献类型：
--
作者：
Nho RS;Peterson M;Hergert P;Henke CA
特发性肺纤维化是一种致死性的纤维性疾病，其特征是成纤维细胞在I型胶原基质中持续增殖，导致纤维组织的网状网络扩大。然而，肌成纤维细胞在IPF中持续存在的潜在机制仍不清楚。在正常的组织修复过程中，不需要的成纤维细胞在胶原-基质收缩过程中被消除，其机制是高PTEN活性抑制Akt。我们先前已经发现，在IPF成纤维细胞中，由于PTEN活性过低而导致PI3K/Akt活性异常高，导致凋亡诱导蛋白转录激活因子FOXO3a失活。在这里，我们证明了这种低FOXO3a活性使IPF成纤维细胞对胶原介导的凋亡具有抵抗力。我们表明，低FOXO3a活性使IPF成纤维细胞具有抗凋亡表型的机制包括通过PTEN/Akt依赖的途径下调Cav-1的表达，从而抑制Fas的表达。我们证明，PTEN过表达或Akt抑制增加了IPF成纤维细胞中FOXO3a的表达，导致小窝蛋白-1的上调。我们发现FOXO3a与Cav-1启动子区域结合，并且FOXO3a的异位表达在转录上增加了Cav-1mRNA和蛋白的表达。反过来，我们发现小窝蛋白-1的过表达增加了Fas水平和caspase-3/7的活性，并促进了聚合的I型胶原上的IPF成纤维细胞的凋亡。我们发现IPF患者成纤维细胞灶内成纤维细胞中小窝蛋白-1、Fas和裂解的caspase-3蛋白的表达很低。我们的数据表明，病理改变的PTEN/Akt轴使FOXO3a失活，下调Cav-1和Fas的表达。这使IPF成纤维细胞具有抗凋亡表型，并可能与IPF的进展有关。
Idiopathic Pulmonary Fibrosis is a lethal fibrotic disease characterized by the unrelenting proliferation and persistence of fibroblasts in a type I collagen-rich matrix that result in an expanding reticular network of fibrotic tissue. However, the underlying mechanism responsible for the persistence of myofibroblasts in IPF remains unclear. During normal tissue repair, unwanted fibroblasts are eliminated during collagen-matrix contraction by a mechanism whereby high PTEN activity suppresses Akt. We have previously found that FoxO3a, a transcriptional activator of apoptosis-inducing proteins, is inactivated in IPF fibroblasts resulting from aberrantly high PI3K/Akt activity due to inappropriately low PTEN activity. Here we demonstrate that this low FoxO3a activity confers IPF fibroblasts with resistance to collagen-mediated apoptosis. We show that the mechanism by which low FoxO3a activity confers IPF fibroblasts with an apoptotic resistant phenotype involves suppression of Fas expression as a result of down regulation of cav-1 expression via a PTEN/Akt-dependent pathway. We demonstrate that PTEN over-expression or Akt inhibition increases FoxO3a expression in IPF fibroblasts, resulting in up-regulation of caveolin-1. We show that FoxO3a binds to the cav-1 promoter region and ectopic expression of FoxO3a transcriptionally increases cav-1 mRNA and protein expression. In turn, we show that overexpression of caveolin-1 increases Fas levels and caspase-3/7 activity and promotes IPF fibroblast apoptosis on polymerized type I collagen. We have found that the expression of caveolin-1, Fas and cleaved caspase-3 proteins in fibroblasts within the fibroblastic foci of IPF patient specimens is low. Our data indicate that the pathologically altered PTEN/Akt axis inactivates FoxO3a down-regulating cav-1 and Fas expression. This confers IPF fibroblasts with an apoptosis-resistant phenotype and may be responsible for IPF progression.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
29
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
通讯作者：
White MF
影响因子：
4.8
作者：
Cichy, SB;Uddin, S;Unterman, TG
通讯作者：
Unterman, TG
DOI：
10.2217/14796694.2.1.83
发表时间：
2006-02-01
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Huang, Haojie;Tindall, Donald J
通讯作者：
Tindall, Donald J
影响因子：
64.8
作者：
Naka, Kazuhito;Hoshii, Takayuki;Hirao, Atsushi
通讯作者：
Hirao, Atsushi