Compensation of the AKT signaling by ERK signaling in transgenic mice hearts overexpressing TRIM72
Compensation of the AKT signaling by ERK signaling in transgenic mice hearts overexpressing TRIM72
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DOI：
10.1016/j.yexcr.2013.02.016
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发表时间：
2013-06-10
影响因子：
3.7
通讯作者：
Mahoney, Sarah Jane
中科院分区：
文献类型：
--
作者：
Ham, Young-Mi;Mahoney, Sarah Jane
已知AKT和ERIC信号通路参与细胞肥大、增殖、存活和分化。虽然有证据表明这两个信号通路之间的串扰在细胞，有较少的证据串扰在体内。在这里，我们表明，ART和ERR信号之间的串扰在TRIM 72过表达转基因小鼠（TRIM 72-Tg）与α-MHC启动子调节和维持他们的心脏大小。TRIM 72是一种心脏和骨骼肌特异性蛋白，通过IRS-1降解下调AKT-mTOR信号传导，并减少大鼠心肌细胞的大小和出生后TRIM 72-Tg心脏的大小。TRIM 72表达上调心肌细胞肥大诱导剂，而IRS-1下调IGF-1。TRIM 72特异性调节IGF-1依赖的AKT-mTOR信号传导，导致心肌细胞的大小减小。出生后TRIM 72-Tg心脏小于对照组，抑制AKT-mTOR信号传导。然而，尽管抑制了AKT-mTOR信号传导，但成年TRIM 72-Tg心脏比对照大。在成年TRIM 72-Tg中观察到ERIC、PKC-α和JNK的活化升高，并且这些信号由ET-1通过ET受体A和B介导。总之，这些结果表明，AKT信号传导在生理条件下调节心脏肥大，并且ERR信号传导补偿TRIM 72过表达期间ART信号传导的缺失，导致病理性肥大。(C)2013 Elsevier Inc. All rights reserved.
The AKT and ERIC signaling pathways are known to be involved in cell hypertrophy, proliferation, survival and differentiation. Although there is evidence for crosstalk between these two signaling pathways in cellulo, there is less evidence for cross talk in vivo. Here, we show that crosstalk between ART and ERR signaling in the hearts of TRIM72-overexpressing transgenic mice (TRIM72-Tg) with alpha-MHC promoter regulates and maintains their heart size. TRIM72, a heart- and skeletal muscle-specific protein, downregulates AKT-mTOR signaling via IRS-1 degradation and reduces the size of rat cardiomyocytes and the size of postnatal TRIM72-Tg hearts. TRIM72 expression was upregulated by hypertrophic inducers in cardiomyocytes, while IRS-1 was downregulated by IGF-1. TRIM72 specifically regulated IGF-1-dependent AKT-mTOR signaling, resulting in a reduction of the size of cardiomyocytes. Postnatal TRIM72-Tg hearts were smaller than controltreated hearts with inhibition of AKT-mTOR signaling. However, adult TRIM72-Tg hearts were larger than of control despite the suppression of AKT-mTOR signaling. Activation of ERIC, PKC-alpha, and JNK were observed to be elevated in adult TRIM72-Tg, and these signals were mediated by ET-1 via the ET receptors A and B. Altogether, these results suggest that AKT signaling regulates cardiac hypertrophy in physiological conditions, and ERR signaling compensates for the absence of ART signaling during TRIM72 overexpression, leading to pathological hypertrophy. (C) 2013 Elsevier Inc. All rights reserved.