REGULATION OF 4F2 HEAVY-CHAIN GENE-EXPRESSION DURING NORMAL HUMAN T-CELL ACTIVATION CAN BE MEDIATED BY MULTIPLE DISTINCT MOLECULAR MECHANISMS
REGULATION OF 4F2 HEAVY-CHAIN GENE-EXPRESSION DURING NORMAL HUMAN T-CELL ACTIVATION CAN BE MEDIATED BY MULTIPLE DISTINCT MOLECULAR MECHANISMS
复制标题
DOI：
10.1128/mcb.8.9.3820
复制
发表时间：
1988-09-01
影响因子：
5.3
通讯作者：
LEIDEN, JM
中科院分区：
文献类型：
--
作者：
LINDSTEN, T;JUNE, CH;LEIDEN, JM
4F2 分子属于凝集素或抗原介导的 T 细胞激活后诱导的一组细胞表面抗原。凝集素介导的刺激后 4F2 细胞表面表达的增加已被证明伴随着 4F2 重链 (4F2HC) mRNA 稳态水平的平行增加。本报告中描述的研究旨在进一步阐明在正常静息人外周血 T 细胞激活后诱导 4F2HC 基因表达的分子机制。静息 T 细胞中成熟 4F2HC mRNA 的低水平被证明是 4F2HC 基因的外显子 1-内含子 1 区域内转录延伸受阻的结果，而不是启动子失活的结果。佛波醇肉豆蔻酸酯醋酸酯对静息 T 细胞的刺激导致稳态 4F2HC mRNA 水平增加 20 倍，这是通过去除转录延伸阻断来介导的。佛波醇肉豆蔻酸酯乙酸酯诱导的 4F2HC 基因表达增加与之前描述的 AP-1 介导的佛波醇酯诱导的基因表达不同，因为它需要新的蛋白质合成。用离子霉素加 PMA 处理静息 T 细胞导致 4F2HC mRNA 水平增加 60 倍。这种诱导是通过启动子利用率的增加和转录延伸阻断的去除来介导的。最后，通过延长 4F2HC mRNA 的半衰期，放线菌酮处理静息 T 细胞诱导 4F2HC 基因表达水平增加约五倍，尽管这一机制的生理意义仍不清楚。这些结果表明，正常外周血T细胞中4F2HC基因表达水平可以通过至少三种不同的分子途径调节：（i）启动子利用的变化，（ii）转录延伸阻断的调节，以及（iii）mRNA稳定性的改变。
The 4F2 molecule belongs to the set of cell surface antigens which is induced following lectin- or antigen-mediated T-cell activation. The increase in 4F2 cell surface expression following lectin-mediated stimultion has been shown to be accompanied by a parallel increase in the steady-state levels of 4F2 heavy-chain (4F2HC) mRNA. The studies described in this report were designed to further elucidate the molecular mechanisms responsible for induction of 4F2HC gene expression following activation of normal resting human peripheral blood T cells. The low levels of mature 4F2HC mRNA in resting T cells were shown to be the result of a block to transcription elongation within the exon 1-intron 1 region of the 4F2HC gene rather than promoter inactivity. Phorbol myristate acetate stimulation of resting T cells resulted in a 20-fold increase in steady-state 4F2HC mRNA levels which was mediated by removal of this block to transcription elongation. The phorbol myristate acetate-induced increase in 4F2HC gene expression is distinct from previously described AP-1-mediated, phorbol ester-induced gene expression in that it requires new protein synthesis. Treatment of resting T cells with ionomycin plus PMA resulted in a 60-fold increase in 4F2HC mRNA levels. This induction was mediated by both an increase in promoter utilization and removal of the block to transcription elongation. Finally, by increasing the half-life of 4F2HC mRNA, cycloheximide treatment of resting T cells induced an approximately fivefold increase in the levels of 4F2HC gene expression, although the physiologic significance of this mechanism remains unclear. These results demonstrate that the level of 4F2HC gene expression in normal peripheral blood T cells can be regulated by at least three distinct molecular pathways: (i) changes in promoter utilization,(ii) modulation of a block to transcription elongation, and (iii) alterations in mRNA stability.