Feldman G M, Petricoin E F, David M, Larner A C, Finbloom D S
Division of Cytokine Biology, Food and Drug Administration, Bethesda, Maryland 20892.
J Biol Chem. 1994 Apr 8;269(14):10747-52.
Interleukin-6, leukemia inhibitory factor, and oncostatin M exert a broad range of similar biological activities through association of their receptors with the signal-transducing component gp130. Although it is known that these cytokines trigger rapid tyrosine phosphorylation of a common set of cellular proteins as well as induction of several of the same early response genes, the mechanisms by which these genes are activated is not well understood. In this report, we show that interleukin-6, leukemia inhibitory factor, and oncostatin M stimulate the assembly of protein complexes that recognize conserved sequences within the enhancers of two genes (interferon regulatory factor 1 and Fc gamma receptor type I) that are rapidly activated by these cytokines. These enhancers are known to be required for transcriptional induction of these genes by interferon-gamma. Assembly of the DNA-binding protein complexes occurs within minutes after ligand addition and depends upon tyrosine phosphorylation. These complexes contain the p91 transcription factor, which is tyrosine-phosphorylated in response to these cytokines. An additional tyrosine-phosphorylated protein of 93 kDa can be coimmunoprecipitated with antibodies against p91. These findings further expand the network of cytokines known to activate p91 and, in addition, support the concept that sets of tyrosine-phosphorylated proteins may be responsible for the cytokine-regulated expression of early response genes.
白细胞介素-6、白血病抑制因子和抑瘤素M通过其受体与信号转导成分gp130结合发挥广泛的相似生物学活性。尽管已知这些细胞因子可触发一组共同的细胞蛋白的快速酪氨酸磷酸化以及诱导几个相同的早期反应基因，但这些基因被激活的机制尚不清楚。在本报告中，我们表明白细胞介素-6、白血病抑制因子和抑瘤素M刺激蛋白质复合物的组装，这些复合物识别两个基因（干扰素调节因子1和I型Fcγ受体）增强子内的保守序列，这两个基因可被这些细胞因子快速激活。已知这些增强子是干扰素-γ诱导这些基因转录所必需的。DNA结合蛋白复合物的组装在添加配体后几分钟内发生，并依赖于酪氨酸磷酸化。这些复合物包含p91转录因子，其在响应这些细胞因子时发生酪氨酸磷酸化。一种额外的93 kDa酪氨酸磷酸化蛋白可与抗p91抗体共免疫沉淀。这些发现进一步扩展了已知可激活p91的细胞因子网络，此外，支持了酪氨酸磷酸化蛋白组可能负责细胞因子调节的早期反应基因表达的概念。
