ERK, p38, and Smad signaling pathways differentially regulate transforming growth factor-beta1 autoinduction in proximal tubular epithelial cells.
ERK, p38, and Smad signaling pathways differentially regulate transforming growth factor-beta1 autoinduction in proximal tubular epithelial cells.
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ERK、p38 和 Smad 信号通路差异调节近端肾小管上皮细胞中的转化生长因子-β1 自诱导。
DOI：
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发表时间：
2006
影响因子：
6
通讯作者：
A. Phillips
中科院分区：
文献类型：
--
作者：
M. Zhang;D. Fraser;A. Phillips
转化生长因子（TGF）-β 1是与进行性肾病相关的纤维化的最终共同途径的介体，已知近端肾小管细胞（PTC）在该过程中发挥重要作用。当前研究的目的是探讨PTC TGF-β 1自身诱导的机制。添加TGF-β 1导致TGF-β 1 mRNA的量增加，并增加从头蛋白质合成。TGF-β 1的加入导致R-Smads磷酸化增加，细胞外信号调节激酶促分裂原活化蛋白（MAP）激酶和p38 MAP激酶途径活化。使用显性负性Smad 3（Smad 3 DN）表达载体，Smad 3小干扰RNA，并与化学抑制剂PD 98059或SB 203580的细胞外信号调节激酶和p38 MAP激酶通路的抑制表明，这些信号通路的激活独立发生。Smad 3 DN表达、Smad 3小干扰RNA或加入PD 98059抑制TGF-β 1依赖性刺激TGF-β 1 mRNA。此外，Smad 3阻断特异性抑制TGF-β 1对转录因子AP-1的激活，而PD 98059阻止TGF-β 1依赖性核因子-κ B的激活。相反，抑制p38 MAP激酶抑制从头TGF-β 1蛋白合成，但不影响TGF-β 1 mRNA表达或激活的转录因子。总之，在PTC中，TGF-β 1自身诱导需要独立调节的Smad和非Smad通路的协调作用。此外，这些途径调节TGF-β 1合成的不同转录和翻译组分。
Transforming growth factor (TGF)-beta1 is a mediator of the final common pathway of fibrosis associated with progressive renal disease, a process in which proximal tubular cells (PTCs) are known to play an important part. The aim of the current study was to examine the mechanism of PTC TGF-beta1 autoinduction. The addition of TGF-beta1 led to increased amounts of TGF-beta1 mRNA and increased de novo protein synthesis. The addition of TGF-beta1 led to increased phosphorylation of R-Smads and activation of extracellular signal-regulated kinase mitogen-activated protein (MAP) kinase and p38 MAP kinase pathways. Use of a dominant-negative Smad3 (Smad3 DN) expression vector, Smad3 small interfering RNA, and inhibition of extracellular signal-regulated kinase and p38 MAP kinase pathways with the chemical inhibitors PD98059 or SB203580 suggested that activation of these signaling pathways occurred independently. Smad3 DN expression, Smad3 small interfering RNA, or the addition of PD98059 inhibited TGF-beta1-dependent stimulation of TGF-beta1 mRNA. Furthermore, Smad3 blockade specifically inhibited activation of the transcription factor AP-1 by TGF-beta1, whereas PD98059 prevented TGF-beta1-dependent nuclear factor-kappaB activation. In contrast inhibition of p38 MAP kinase inhibited de novo TGF-beta1 protein synthesis but did not influence TGF-beta1 mRNA expression or activation of either transcription factor. In summary, in PTCs, TGF-beta1 autoinduction requires the coordinated action of independently regulated Smad and non-Smad pathways. Furthermore these pathways regulate distinct transcriptional and translational components of TGF-beta1 synthesis.
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DOI：
10.1073/pnas.120055097
发表时间：
2000-07-05
影响因子：
11.1
作者：
Ziyadeh, FN;Hoffman, BB;Sharma, K
通讯作者：
Sharma, K
影响因子：
19.6
作者：
BORDER, WA;NOBLE, NA;KAGAMI, S
通讯作者：
KAGAMI, S
影响因子：
19.6
作者：
RYAN, MJ;JOHNSON, G;TOROKSTORB, B
通讯作者：
TOROKSTORB, B
影响因子：
6
作者：
Yang, JW;Liu, YH
通讯作者：
Liu, YH
DOI：
10.1073/pnas.96.9.4844
发表时间：
1999-04-27
影响因子：
11.1
作者：
Liberati, NT;Datto, MB;Wang, XF
通讯作者：
Wang, XF