The inhibition of CMV promoter by heat shock factor 4b is regulated by Daxx.
The inhibition of CMV promoter by heat shock factor 4b is regulated by Daxx.
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热休克因子 4b 对 CMV 启动子的抑制受 Daxx 调节。
DOI：
10.1016/j.biocel.2010.06.024
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发表时间：
2010-10
期刊：
影响因子：
--
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中科院分区：
文献类型：
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热休克因子4（Heat shock factor 4，Hsf 4 b）是一种新的白内障发生蛋白，其突变与人类和动物的遗传性白内障密切相关。在透镜发育过程中，它作为转录激活因子和转录抑制因子调节其下游靶点。然而，调节Hsf 4 b转录活性的信号传导因子仍然没有完全确定。在这里，我们发现Hsf 4 b，而不是Hsf 4 a（Hsf 4的另一种亚型），在Hsf 4 −/−小鼠透镜上皮细胞系（mLEC/hsf 4 −/−）中作为CMV启动子的抑制剂以及Hsp 25的激活剂。Hsf 4 b通过与CMV启动子中173- 176 bp的TTCC（HSE基序）直接结合来抑制CMV启动子活性。Hsf 4 b/S299在PDSM基序中的磷酸化参与CMV启动子的负调控，而Hsf 4a中不存在该磷酸化。Hsf 4 b的转录抑制与转录抑制因子Daxx有关。Hsf 4 b可以与Daxx相互作用并共定位于细胞核中，并且它们的缔合通过Hsf 4 b/S299的磷酸化来调节。此外，我们发现Hsf 4a和Hsf 1也与Daxx相关。然而，与激活Hsf 1相反，Daxx可以抑制mLEC/hsf 4 −/−细胞系中Hsf 4 b诱导的Hsp 25表达。我们的研究结果表明，Hsf 4 b的转录抑制功能是由Hsf 4 b/S299的磷酸化和磷酸化依赖性协会与Daxx。
Heat shock factor 4 (Hsf4b) has been identified as a novel cataractogenic protein whose mutation has been closely associated with hereditary cataracts in humans and animals. It acts both as a transcription activator and a transcription inhibitor in the regulation of its downstream targets during lens development. However, the signaling factors that regulate Hsf4b transcription activity are still not completely defined. Here, we found that Hsf4b, not Hsf4a (another isoform of Hsf4), acts as the inhibitor of CMV promoter as well as the activator of Hsp25 in the Hsf4−/− mouse lens epithelial cell line (mLEC/hsf4−/−). Hsf4b inhibits CMV-promoter activity by directly binding to TTCC (HSE motif) at 173–176bps in the CMV promoter. The phosphorylation of Hsf4b/S299 in the PDSM motif, which is absent in Hsf4a, participates in the negative regulation of the CMV promoter. The transcriptional inhibition of Hsf4b is associated with transcriptional inhibitor Daxx. Hsf4b can interact and co-localize with Daxx in the nucleus, and their association is regulated by the phosphorylation of Hsf4b/S299. In addition, we found that Hsf4a and Hsf1 were also associated with Daxx. However, in contrast to activating Hsf1, Daxx can repress Hsf4b-induced expression of Hsp25 in the mLEC/hsf4−/− cell line. Our results demonstrate that the transcription-inhibitory function of Hsf4b is regulated by the phosphorylation of Hsf4b/S299 and phosphorylation-dependent association with Daxx.
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DOI：
10.1073/pnas.75.11.5291
发表时间：
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