TGFβ- and bleomycin-induced extracellular matrix synthesis is mediated through Akt and mammalian target of rapamycin (mTOR).
TGFβ- and bleomycin-induced extracellular matrix synthesis is mediated through Akt and mammalian target of rapamycin (mTOR).
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TGFβ-和博来霉素诱导的细胞外基质合成是通过雷帕霉素（MTOR）的Akt和哺乳动物靶标介导的。
DOI：
10.1002/jcp.22648
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发表时间：
2011-11
影响因子：
5.6
通讯作者：
Somanath, Payaningal R.
中科院分区：
文献类型：
--
作者：
Goc, Anna;Choudhary, Mrunal;Byzova, Tatiana V.;Somanath, Payaningal R.
许多促纤维化刺激物，如生长因子、细胞因子和细胞外基质（ECM）蛋白，涉及Akt及其下游底物介导它们的作用。我们以前报道过，Akt 1是血管细胞中三个基因Akt家族的主要亚型，Akt 1的缺失导致皮肤和血管系统中ECM重塑受损。在当前的研究中，我们研究了Akt 1在TGFβ和博来霉素诱导的成纤维细胞ECM蛋白合成和分泌中的重要性。我们观察到TGFβ和博莱霉素都以剂量和时间依赖性方式刺激ECM蛋白的合成。用TGFβ和博来霉素处理还导致Akt、雷帕霉素的哺乳动物靶标（mTOR）及其下游信号传导伴侣p70 S6激酶、核糖体S6蛋白和4 E-BP 1的磷酸化增加，从而导致该途径的激活。TGFβ和博来霉素对ECM合成的影响通过用mTOR抑制剂雷帕霉素预处理而减弱。mTOR负责许多ECM蛋白、粘附分子和基质金属蛋白酶（MMP）的转录调节，而成纤维细胞响应TGFβ和博来霉素的主要ECM蛋白如纤连蛋白和胶原（I、II和V型）的合成在翻译水平上由mTOR调节。这些发现表明Akt-mTOR信号通路在体内TGF介导的纤维化事件中的重要性。
A number of pro-fibrogenic stimuli, such as growth factors, cytokines and extracellular matrix (ECM) proteins, involve Akt and its downstream substrates in mediating their effects. We previously reported that absence of Akt1, which is the predominant isoform of the three gene Akt family in vascular cells, resulted in impaired ECM remodeling in skin and vasculature. In the current study, we investigated the importance of Akt1 in TGFβ-and bleomycin-induced synthesis and secretion of ECM proteins by fibroblasts. We observed that both TGFβ and bleomycin stimulated the synthesis of ECM proteins in a dose- and time-dependent manner. Treatment with TGFβ and bleomycin also resulted in increased phosphorylation of Akt, mammalian target of rapamycin (mTOR) and their downstream signaling partners, p70S6 Kinase, Ribosomal S6 protein and 4E-BP1, resulting in the activation of this pathway. The effects of TGFβ and bleomycin on ECM synthesis were blunted by pre-treatment with an mTOR inhibitor rapamycin. Whereas mTOR is responsible for the transcriptional regulation of a number of ECM proteins, adhesion molecules and matrix metalloproteases (MMPs), synthesis of major ECM proteins such as fibronectin and collagens (types I, II and V) by fibroblasts in response to TGFβ and bleomycin is regulated by mTOR at the translational level. These findings indicate the importance of the Akt-mTOR signaling pathway in TGF-mediated fibrogenic events in vivo.
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影响因子：
82.9
作者：
Chen, JH;Somanath, PR;Byzova, TV
通讯作者：
Byzova, TV
影响因子：
3.7
作者：
Seet LF;Su R;Barathi VA;Lee WS;Poh R;Heng YM;Manser E;Vithana EN;Aung T;Weaver M;Sage EH;Wong TT
通讯作者：
Wong TT
DOI：
10.1126/science.1176009
发表时间：
2009-11-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hynes RO
通讯作者：
Hynes RO
影响因子：
7.5
作者：
Kadler KE;Hill A;Canty-Laird EG
通讯作者：
Canty-Laird EG
影响因子：
5.8
作者：
Paulissen G;Rocks N;Gueders MM;Crahay C;Quesada-Calvo F;Bekaert S;Hacha J;El Hour M;Foidart JM;Noel A;Cataldo DD
通讯作者：
Cataldo DD