Jamal S, Ziff E
Department of Biochemistry, New York University Medical Center, New York 10016.
Nature. 1990 Mar 29;344(6265):463-6. doi: 10.1038/344463a0.
A primary response to many growth factor-induced transmembrane signals is the rapid activation of transcription of the proto-oncogene c-fos and other early-response genes, including the beta-actin gene. The c-raf gene encodes a cytoplasmic serine/threonine kinase, raf-1, whose activity is also responsive to transmembrane signals and which in mutant form can transform cells. Here we show that in transient assays, the v-raf protein, which is a constitutively activated oncogenic counterpart of raf-1, can transactivate transcription from two early-response promoters, including the c-fos promoter from human and murine cells and the human beta-actin gene promoter. Multiple elements of the human fos promoter, including the dyad symmetry element necessary for growth-factor induction, an octanucleotide direct repeat element, and the region spanning the sequence from nucleotides -225 to -99 can all serve as targets for raf induction. The c-myc promoter and two adenovirus-2 early promoters are not induced. These findings indicate that raf kinase, when activated by a transmembrane signal or by mutation of a regulatory domain, can phosphorylate a factor(s) capable of regulating transcription of the c-fos and actin genes. The oncogenic form of raf may transform by constitutively activating early response protooncogenes such as c-fos.
对许多生长因子诱导的跨膜信号的主要反应是原癌基因c-fos和其他早期反应基因（包括β-肌动蛋白基因）转录的快速激活。c-raf基因编码一种细胞质丝氨酸/苏氨酸激酶raf-1，其活性也对跨膜信号有反应，并且其突变形式可转化细胞。在这里我们表明，在瞬时分析中，v-raf蛋白作为raf-1的组成型激活致癌对应物，可从两个人类和鼠类细胞的早期反应启动子（包括c-fos启动子）以及人类β-肌动蛋白基因启动子反式激活转录。人类fos启动子的多个元件，包括生长因子诱导所需的二元对称元件、一个八核苷酸直接重复元件以及跨越从核苷酸-225至-99的序列区域，均可作为raf诱导的靶标。c-myc启动子和两个腺病毒2早期启动子未被诱导。这些发现表明，raf激酶在被跨膜信号激活或通过调节结构域的突变激活时，可磷酸化能够调节c-fos和肌动蛋白基因转录的一个或多个因子。raf的致癌形式可能通过组成型激活早期反应原癌基因（如c-fos）来实现转化。
