Lee H Y, Walsh G L, Dawson M I, Hong W K, Kurie J M
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Biol Chem. 1998 Mar 20;273(12):7066-71. doi: 10.1074/jbc.273.12.7066.
Retinoids, including retinol and retinoic acid derivatives, inhibit the growth of normal human bronchial epithelial (HBE) cells. The signaling pathways through which retinoids mediate this effect have not been defined. Normal HBE cell growth is stimulated by treatment with a variety of growth factors that increase mitogen-activated protein (MAP) activity. In this study, we examined MAP kinase-dependent pathways as potential targets of retinoid signaling and the role of MAP kinases in retinoid-induced c-fos gene regulation. All-trans-retinoic acid (t-RA) inhibited Jun N-terminal kinase (JNK) and, to a lesser extent, extracellular signal-regulated kinase activity in normal HBE cells. t-RA reduced c-fos mRNA and protein levels by decreasing c-fos gene transcription. The c-fos promoter was activated by co-transfection with a constitutively active JNK kinase (SEK)-1 and suppressed by a dominant negative JNK kinase kinase (MEKK)-1. Furthermore, c-fos expression was inhibited by agonists of retinoic acid receptors (RARs) or retinoid X receptors (RXRs), and suppression of c-fos promoter activity by t-RA was abrogated by treatment with antagonists of RAR-alpha or of all the RXRs. These findings provide the first evidence that t-RA inhibits JNK activity and demonstrate a potential role of JNK-dependent pathways in the suppression of c-fos expression by t-RA. Furthermore, c-fos expression was inhibited through activation of RAR- and RXR-dependent signaling pathways. In light of the growth activation induced by JNK/SEK-dependent pathways in a variety of cells, these data support further investigation into the role of JNK-dependent signaling in the growth-suppressive effects of retinoids.
维甲酸，包括视黄醇和维甲酸衍生物，可抑制正常人支气管上皮（HBE）细胞的生长。维甲酸介导这种效应的信号通路尚未明确。多种生长因子处理可刺激正常HBE细胞生长，这些生长因子会增加丝裂原活化蛋白（MAP）活性。在本研究中，我们研究了MAP激酶依赖性通路作为维甲酸信号潜在靶点的情况，以及MAP激酶在维甲酸诱导的c-fos基因调控中的作用。全反式维甲酸（t-RA）可抑制正常HBE细胞中的Jun N端激酶（JNK），并在较小程度上抑制细胞外信号调节激酶活性。t-RA通过降低c-fos基因转录来降低c-fos mRNA和蛋白水平。c-fos启动子与组成型活性JNK激酶（SEK）-1共转染时被激活，而被显性负性JNK激酶激酶（MEKK）-1抑制。此外，维甲酸受体（RARs）或维甲酸X受体（RXRs）的激动剂可抑制c-fos表达，用RAR-α拮抗剂或所有RXRs拮抗剂处理可消除t-RA对c-fos启动子活性的抑制作用。这些发现首次证明t-RA可抑制JNK活性，并证明JNK依赖性通路在t-RA抑制c-fos表达中可能发挥的作用。此外，c-fos表达通过RAR和RXR依赖性信号通路的激活而受到抑制。鉴于JNK/SEK依赖性通路在多种细胞中诱导生长激活，这些数据支持进一步研究JNK依赖性信号在维甲酸生长抑制作用中的作用。
