Bishopric N H, Jayasena V, Webster K A
Life Sciences Division, SRI International, Menlo Park, California 94025.
J Biol Chem. 1992 Dec 15;267(35):25535-40.
Transcription of the skeletal alpha-actin gene is selectively activated in rat myocardiocytes undergoing hypertrophy both in vivo and in vitro. In most of these models, transient expression of certain proto-oncogene transcription factors precedes hypertrophy and sarcomeric gene induction. Using expression vectors encoding Fos and Jun, the main constituents of transcriptional activator protein AP-1, we analyzed the role of these oncoproteins in mediating the transcriptional induction of skeletal alpha-actin by adrenergic stimulation. Both c-fos and c-jun were induced early after beta-adrenergic stimulation, with peak mRNA levels preceding skeletal alpha-actin induction by several hours. A second peak of c-jun mRNA coincided with skeletal alpha-actin induction. Co-transfection assays in cardiac myocytes and P19 teratocarcinoma cells demonstrated that over-expression of c-jun, or c-fos plus c-jun, transactivated the skeletal alpha-actin promoter by about 5-fold. Comparable activation was not seen for alpha-myosin heavy chain or cardiac alpha-actin promoters. Skeletal alpha-actin promoter sequences between -153 and -36 were required for maximal transactivation by c-fos/c-jun, and purified Fos and Jun were bound specifically within this region. A direct physiological role is suggested for the AP-1 transcription factor complex in regulating skeletal alpha-actin gene expression and alpha-actin isoform switching during the onset of signal-mediated cardiac myocyte hypertrophy.
在体内和体外经历肥大的大鼠心肌细胞中，骨骼肌α-肌动蛋白基因的转录被选择性激活。在大多数这些模型中，某些原癌基因转录因子的瞬时表达先于肥大和肌节基因诱导。利用编码转录激活蛋白AP-1的主要成分Fos和Jun的表达载体，我们分析了这些癌蛋白在介导肾上腺素能刺激对骨骼肌α-肌动蛋白的转录诱导中的作用。β-肾上腺素能刺激后早期即可诱导c-fos和c-jun，其mRNA水平峰值比骨骼肌α-肌动蛋白诱导提前数小时。c-jun mRNA的第二个峰值与骨骼肌α-肌动蛋白诱导同时出现。心肌细胞和P19畸胎癌细胞中的共转染试验表明，c-jun或c-fos加c-jun的过表达可使骨骼肌α-肌动蛋白启动子反式激活约5倍。α-肌球蛋白重链或心肌α-肌动蛋白启动子未见类似激活。c-fos/c-jun最大反式激活需要-153至-36之间的骨骼肌α-肌动蛋白启动子序列，纯化的Fos和Jun可特异性结合在该区域内。提示AP-1转录因子复合物在信号介导的心肌细胞肥大发生过程中调节骨骼肌α-肌动蛋白基因表达和α-肌动蛋白异构体转换中具有直接的生理作用。
