Gene-specific recruitment of positive and negative elongation factors during stimulated transcription of the MKP-1 gene in neuroendocrine cells.
Gene-specific recruitment of positive and negative elongation factors during stimulated transcription of the MKP-1 gene in neuroendocrine cells.
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DOI：
10.1093/nar/gkl1138
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发表时间：
2007
影响因子：
14.9
通讯作者：
Schlegel W
中科院分区：
文献类型：
--
作者：
Fujita T;Ryser S;Tortola S;Piuz I;Schlegel W
MAP激酶磷酸酶-1（MKP-1）控制核MAP激酶活性，对细胞生长或凋亡具有重要影响。MKP-1转录组成型启动，但延伸在外显子1内被阻断。目前尚不清楚MKP-1的诱导是如何控制的。在这里，我们报告的转录延伸因子P-TEFb，DSIF和NELF调节MKP-1在垂体GH4 C1细胞系的转录。在刺激之前，DSIF、NELF和RNA聚合酶II（pol II）与延伸阻断位点上游的MKP-1基因的启动子近端区域相关联。促甲状腺激素释放激素（TRH）导致P-TEFb沿着整个基因募集，并且延伸阻断位点下游的DSIF和pol II显著增加，而NELF仍然局限于启动子近端区域。5，6-二氯-1-β-d-呋喃核糖基苯并咪唑（DRB）是P-TEFb的抑制剂，它消除了TRH对MKP-1转录的刺激。DRB特异性抑制TRH诱导的DSIF和P-TEFb向MKP-1基因的募集。此外，DRB治疗消除TRH诱导的进展沿着MKP-1基因的pol II磷酸化的Ser-2的CTD。这些结果表明，P-TEFb是必要的基因特异性刺激的转录延伸在哺乳动物细胞中通过机制，涉及激活DSIF-NELF复合物和Ser-2磷酸化的pol II。
MAP kinase phosphatase-1 (MKP-1) controls nuclear MAP kinase activity with important consequences on cell growth or apoptosis. MKP-1 transcription is initiated constitutively but elongation is blocked within exon 1. It is unclear how induction of MKP-1 is controlled. Here, we report that the transcriptional elongation factors P-TEFb, DSIF and NELF regulate MKP-1 transcription in the pituitary GH4C1 cell line. Prior to stimulation, DSIF, NELF and RNA polymerase II (pol II) associate with the promoter-proximal region of the MKP-1 gene upstream of the elongation block site. Thyrotropin-releasing hormone (TRH) leads to recruitment of P-TEFb along the whole gene and a marked increase of DSIF and pol II downstream of the elongation block site, whereas NELF remains confined to the promoter-proximal region. 5,6-Dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) an inhibitor of P-TEFb eliminated TRH stimulation of MKP-1 transcription. DRB specifically inhibited TRH-induced recruitment of DSIF and P-TEFb to the MKP-1 gene. Furthermore, DRB treatment eliminated TRH-induced progression along the MKP-1 gene of pol II phosphorylated on Ser-2 of its CTD. These results indicate that P-TEFb is essential for gene-specific stimulated transcriptional elongation in mammalian cells via mechanisms which involve the activation of the DSIF–NELF complex and Ser-2 phosphorylation of pol II.
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