Deficiency of the transcriptional regulator p8 results in increased autophagy and apoptosis, and causes impaired heart function.
Deficiency of the transcriptional regulator p8 results in increased autophagy and apoptosis, and causes impaired heart function.
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DOI：
10.1091/mbc.e09-09-0818
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发表时间：
2010-04-15
影响因子：
3.3
通讯作者：
Goruppi S
中科院分区：
文献类型：
--
作者：
Kong DK;Georgescu SP;Cano C;Aronovitz MJ;Iovanna JL;Patten RD;Kyriakis JM;Goruppi S
在这项研究中，我们通过p8−/−小鼠，研究了p8在体外和体内自噬中的作用。在这两种情况下，p8的沉默与自噬和凋亡的基础上调有关。在活体中，p8基因敲除小鼠的心脏出现了引起左心功能下降的特征。自噬是一种用于降解和循环细胞质内容物的细胞保护途径。自噬功能障碍与癌症和心肌病有关。在这里，我们展示了转录调控因子p8在自噬中的作用。P8RNA干扰(RNAi)增加了原代心肌细胞、H9C2和U2OS细胞的基础自噬标志物，并降低了自噬诱导后的细胞存活率。这种自噬与caspase激活有关，并被ATG5沉默和药物抑制剂所阻断。FOXO_3转录因子被报道通过增强自噬相关基因的表达来激活自噬。P8基因表达抑制FOXO_3转录活性，p8基因敲除影响FOXO_3核定位。因此，p8 RNAi增加了FOX03与bnip3启动子的结合，bnip3启动子是已知的自噬FOX03靶标，导致更高的bnip3 RNA和蛋白质水平。因此，bnip3基因敲除可恢复细胞活力，阻断p8缺陷细胞的凋亡。在体内，p8−/−小鼠具有更高的自噬能力，并表达更高的心脏BNIP3水平。这些小鼠出现左室壁变薄和心腔扩张，从而导致心功能受损。我们的研究提供了证据，证明了p8依赖的机制通过充当FOXO_3辅阻遏子来调节自噬，这可能与与自噬失调相关的疾病有关，如心血管疾病和癌症。
In this study, we investigate a role for p8 in autophagy in vitro and in vivo, by using p8 −/− mice. In both settings, silencing of p8 is associated with basal up-regulation of autophagy and apoptosis. In vivo, the hearts of p8 knockout mice develop features that provoke a decreased left ventricular functionality. Autophagy is a cytoprotective pathway used to degrade and recycle cytoplasmic content. Dysfunctional autophagy has been linked to both cancer and cardiomyopathies. Here, we show a role for the transcriptional regulator p8 in autophagy. p8 RNA interference (RNAi) increases basal autophagy markers in primary cardiomyocytes, in H9C2 and U2OS cells, and decreases cellular viability after autophagy induction. This autophagy is associated with caspase activation and is blocked by atg5 silencing and by pharmacological inhibitors. FoxO3 transcription factor was reported to activate autophagy by enhancing the expression of autophagy-related genes. P8 expression represses FoxO3 transcriptional activity, and p8 knockdown affects FoxO3 nuclear localization. Thus, p8 RNAi increases FoxO3 association with bnip3 promoter, a known proautophagic FoxO3 target, resulting in higher bnip3 RNA and protein levels. Accordingly, bnip3 knockdown restores cell viability and blocks apoptosis of p8-deficient cells. In vivo, p8 −/− mice have higher autophagy and express higher cardiac bnip3 levels. These mice develop left ventricular wall thinning and chamber dilation, with consequent impaired cardiac function. Our studies provide evidence of a p8-dependent mechanism regulating autophagy by acting as FoxO3 corepressor, which may be relevant for diseases associated with dysregulated autophagy, as cardiovascular pathologies and cancer.
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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：
4.8
作者：
Hoffmeister, A;Ropolo, A;Iovanna, JL
通讯作者：
Iovanna, JL
影响因子：
11.4
作者：
Goruppi, S;Bonventre, JV;Kyriakis, JM
通讯作者：
Kyriakis, JM
影响因子：
13.3
作者：
Hamacher-Brady, Anne;Brady, Nathan R.;Gustafsson, Asa B.
通讯作者：
Gustafsson, Asa B.
影响因子：
5.3
作者：
Goruppi, Sandro;Patten, Richard D.;Kyriakis, John M.
通讯作者：
Kyriakis, John M.