Liang Qiangrong, Bueno Orlando F, Wilkins Benjamin J, Kuan Chia-Yi, Xia Ying, Molkentin Jeffery D
Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
EMBO J. 2003 Oct 1;22(19):5079-89. doi: 10.1093/emboj/cdg474.
The c-Jun N-terminal kinase (JNK) branch of the mitogen-activated protein kinase (MAPK) signaling pathway regulates cellular differentiation, stress responsiveness and apoptosis in multicellular eukaryotic organisms. Here we investigated the functional importance of JNK signaling in regulating differentiated cellular growth in the post-mitotic myocardium. JNK1/2 gene-targeted mice and transgenic mice expressing dominant negative JNK1/2 were determined to have enhanced myocardial growth following stress stimulation or with normal aging. A mechanism underlying this effect was suggested by the observation that JNK directly regulated nuclear factor of activated T-cell (NFAT) activation in culture and in transgenic mice containing an NFAT-dependent luciferase reporter. Moreover, calcineurin Abeta gene targeting abrogated the pro-growth effects associated with JNK inhibition in the heart, while expression of an MKK7-JNK1 fusion protein in the heart partially reduced calcineurin-mediated cardiac hypertrophy. Collectively, these results indicate that JNK signaling antagonizes the differentiated growth response of the myocardium through direct cross-talk with the calcineurin-NFAT pathway. These results also suggest that myocardial JNK activation is primarily dedicated to modulating calcineurin-NFAT signaling in the regulation of differentiated heart growth.
丝裂原活化蛋白激酶（MAPK）信号通路中的c-Jun氨基末端激酶（JNK）分支，可调节多细胞真核生物中的细胞分化、应激反应和细胞凋亡。在此，我们研究了JNK信号在调节有丝分裂后心肌细胞分化生长中的功能重要性。研究发现，JNK1/2基因敲除小鼠和表达显性负性JNK1/2的转基因小鼠，在应激刺激后或正常衰老过程中，心肌生长增强。在培养物中以及在含有NFAT依赖性荧光素酶报告基因的转基因小鼠中，JNK直接调节活化T细胞核因子（NFAT）的激活，这一观察结果提示了这种效应的潜在机制。此外，钙调神经磷酸酶Aβ基因敲除消除了与心脏中JNK抑制相关的促生长效应，而心脏中MKK7-JNK1融合蛋白的表达部分减轻了钙调神经磷酸酶介导的心脏肥大。总体而言，这些结果表明，JNK信号通过与钙调神经磷酸酶-NFAT途径的直接相互作用，拮抗心肌的分化生长反应。这些结果还表明，心肌JNK激活主要致力于在分化心脏生长的调节中调节钙调神经磷酸酶-NFAT信号。
