Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes
Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes
复制标题
DOI：
10.4049/jimmunol.175.10.6402
复制
发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Graña, X
中科院分区：
文献类型：
--
作者：
Marshall, RM;Salerno, D;Graña, X
刺激原代人T淋巴细胞导致cyclin T1表达上调，这与RNA聚合酶II (RNAP II) c端结构域的磷酸化有关。细胞周期蛋白T1的上调和伴随的细胞周期蛋白依赖性激酶9 （CDK9）的稳定可能促进HIV在活化的T细胞中的生产性复制。我们报道用两种分裂原，PHA和PMA治疗pbl，通过不同的机制导致细胞周期蛋白T1的积累。PHA诱导cyclin T1 mRNA和蛋白的积累，这是cyclin T1 mRNA稳定的结果，而cyclin T1启动子活性没有明显变化。Cyclin T1 mRNA的稳定需要钙调磷酸酶和JNK的激活，因为抑制其中任何一种都可以阻止Cyclin T1的积累。相比之下，PMA通过稳定cyclin T1蛋白诱导cyclin T1蛋白上调，明显独立于蛋白酶体，不积累cyclin T1 mRNA。这一过程依赖于Ca2+非依赖性蛋白激酶C活性，但不需要ERK1/2激活。我们还发现PHA和抗cd3抗体可诱导参与RNAP II c末端结构域磷酸化的细胞周期蛋白/CDK复合物和控制细胞周期进程的G(1)-S细胞周期蛋白的表达。相比之下，PMA单独是G(1)-S细胞周期蛋白表达的较差诱导剂，但在诱导RNAP II细胞周期蛋白/CDK复合物方面通常与PHA一样有效。这些发现表明，RNAP II激酶的表达和激活通过独立刺激基因表达的途径进行协调，但不足以诱导原代T细胞进入S期。
Stimulation of primary human T lymphocytes results in up-regulation of cyclin T1 expression, which correlates with phosphorylation of the C-terminal domain of RNA polymerase II (RNAP II). Up-regulation of cyclin T1 and concomitant stabilization of cyclin-dependent kinase 9 (CDK9) may facilitate productive replication of HIV in activated T cells. We report that treatment of PBLs with two mitogens, PHA and PMA, results in accumulation of cyclin T1 via distinct mechanisms. PHA induces accumulation of cyclin T1 mRNA and protein, which results from cyclin T1 mRNA stabilization, without significant change in cyclin T1 promoter activity. Cyclin T1 mRNA stabilization requires the activation of both calcineurin and JNK because inhibition of either precludes cyclin T1 accumulation. In contrast, PMA induces cyclin T1 protein up-regulation by stabilizing cyclin T1 protein, apparently independently of the proteasome and without accumulation of cyclin T1 mRNA. This process is dependent on Ca2+ independent protein kinase C activity but does not require ERK1/2 activation. We also found that PHA and anti-CD3 Abs induce the expression of both the cyclin/CDK complexes involved in RNAP II C-terminal domain phosphorylation and the G(1)-S cyclins controlling cell cycle progression. In contrast, PMA alone is a poor inducer of the expression of G(1)-S cyclins but often as potent as PHA in inducing RNAP II cyclin/CDK complexes. These findings suggest coordination in the expression and activation of RNAP II kinases by pathways that independently stimulate gene expression but are insufficient to induce S phase entry in primary T cells.