Hsueh Y P, Liang H E, Ng S Y, Lai M Z
Graduate Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
J Immunol. 1997 Jan 1;158(1):85-93.
Cyclic AMP-responsive element binding protein (CREB) mediates gene expression in response to cAMP stimulation. The transcriptional activity of CREB depends on both the phosphorylation of Ser133 and the recruitment of cofactor for assembly of transcriptional complex. Extensive Ser133 phosphorylation of CREB was induced during T cell activation. This phosphorylation event is essential for IL-2 gene expression. However, phosphorylation of CREB at Ser133 was not sufficient for transcriptional activity by CREB. The presence of a second signal from CD28, a potent costimulatory molecule on T cells, stimulated CREB-mediated gene expression. CD28, an effective costimulator of T cell activation and IL-2 gene expression, is shown to induce CREB activation in the presence of anti-CD3 or O-tetradecanoylphorbol 13-acetate. These two signals together stimulated a CRE-dependent reporter gene, the proliferating cell nuclear Ag promoter, and transactivation by the GAL4-CREB fusion protein. Thus optimal induction of CREB, similar to the full activation of T lymphocytes, may be mediated by two distinct signal transductions. Using the specific kinase inhibitor, one of the two pathways appeared to involve mitogen-activated protein kinase kinase but not protein kinase C, protein kinase A, or p70 S6 kinase.
环磷酸腺苷反应元件结合蛋白（CREB）介导基因表达以响应环磷酸腺苷（cAMP）刺激。CREB的转录活性取决于丝氨酸133（Ser133）的磷酸化以及转录复合物组装辅因子的募集。在T细胞活化过程中诱导了CREB广泛的Ser133磷酸化。这一磷酸化事件对于白细胞介素-2（IL-2）基因表达至关重要。然而，CREB在Ser133处的磷酸化不足以使其具有转录活性。来自T细胞上一种有效的共刺激分子CD28的第二种信号的存在，刺激了CREB介导的基因表达。CD28是T细胞活化和IL-2基因表达的有效共刺激因子，在存在抗CD3或十四烷酰佛波醇乙酸酯（O-十四烷酰佛波醇13-乙酸酯）的情况下可诱导CREB活化。这两种信号共同刺激了一种CRE依赖性报告基因、增殖细胞核抗原启动子以及GAL4-CREB融合蛋白的反式激活。因此，与T淋巴细胞的完全活化类似，CREB的最佳诱导可能由两种不同的信号转导介导。使用特异性激酶抑制剂，两条途径之一似乎涉及丝裂原活化蛋白激酶激酶，但不涉及蛋白激酶C、蛋白激酶A或p70核糖体蛋白S6激酶。
