Nemoto S, Sheng Z, Lin A
Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Mol Cell Biol. 1998 Jun;18(6):3518-26. doi: 10.1128/MCB.18.6.3518.
c-Jun N-terminal protein kinase (JNK) and p38, two distinct members of the mitogen-activated protein (MAP) kinase family, regulate gene expression in response to various extracellular stimuli, yet their physiological functions are not completely understood. In this report we show that JNK and p38 exerted opposing effects on the development of myocyte hypertrophy, which is an adaptive physiological process characterized by expression of embryonic genes and unique morphological changes. In rat neonatal ventricular myocytes, both JNK and p38 were stimulated by hypertrophic agonists like endothelin-1, phenylephrine, and leukemia inhibitory factor. Expression of MAP kinase kinase 6b (EE), a constitutive activator of p38, stimulated the expression of atrial natriuretic factor (ANF), which is a genetic marker of in vivo cardiac hypertrophy. Activation of p38 was required for ANF expression induced by the hypertrophic agonists. Furthermore, a specific p38 inhibitor, SB202190, significantly changed hypertrophic morphology induced by the agonists. Surprisingly, activation of JNK led to inhibition of ANF expression induced by MEK kinase 1 (MEKK1) and the hypertrophic agonists. MEKK1-induced ANF expression was also negatively regulated by expression of c-Jun. Our results demonstrate that p38 mediates, but JNK suppresses, the development of myocyte hypertrophy.
c-Jun氨基末端蛋白激酶（JNK）和p38是丝裂原活化蛋白（MAP）激酶家族的两个不同成员，它们可响应各种细胞外刺激来调节基因表达，但其生理功能尚未完全明确。在本报告中，我们发现JNK和p38对心肌细胞肥大的发展具有相反的作用，心肌细胞肥大是一种适应性生理过程，其特征在于胚胎基因的表达和独特的形态变化。在大鼠新生心室肌细胞中，JNK和p38均受到内皮素-1、去氧肾上腺素和白血病抑制因子等肥大激动剂的刺激。p38的组成型激活剂MAP激酶激酶6b（MKK6b）的表达刺激了心房利钠因子（ANF）的表达，ANF是体内心脏肥大的遗传标志物。肥大激动剂诱导的ANF表达需要p38的激活。此外，一种特异性p38抑制剂SB202190显著改变了激动剂诱导的肥大形态。令人惊讶的是，JNK的激活导致MEK激酶1（MEKK1）和肥大激动剂诱导的ANF表达受到抑制。MEKK1诱导的ANF表达也受到c-Jun表达的负调控。我们的结果表明，p38介导但JNK抑制心肌细胞肥大的发展。
