A modified version of a Fos-associated cluster in HBZ affects Jun transcriptional potency
A modified version of a Fos-associated cluster in HBZ affects Jun transcriptional potency
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DOI：
10.1093/nar/gkl375
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发表时间：
2006-01-01
影响因子：
14.9
通讯作者：
Mesnard, Jean-Michel
中科院分区：
文献类型：
--
作者：
Hivin, Patrick;Arpin-Andre, Charlotte;Mesnard, Jean-Michel
像c-Fos，HBZ（HTLV-I bZIP因子）能够与c-Jun相互作用，但在其激活AP-1应答基因的能力上与c-Fos有很大不同，因为HBZ抑制c-Jun的转录活性。为了更好地理解涉及c-Jun活性下调的分子机制，构建了大量HBZ/c-Fos嵌合体并分析了它们与c-Jun相互作用的能力，结合AP-1基序并刺激含有胶原酶启动子的报告基因的表达。通过这种方法，我们证明了HBZ的DNA结合结构域负责其对c-Jun的反式激活潜力的抑制作用。然而，出乎意料的是，我们发现，紧邻DNA接触区的一簇六个带电氨基酸的交换显着改变嵌合体的转录活性。这个特殊的亚结构域可能参与AP-1复合物对转录机制的有效呈递。为了证实这种作用，将HBZ簇中存在的特定残基替换为c-Fos中的相应氨基酸。与野生型HBZ的JunD激活潜力不同，该突变体不再能够刺激JunD活性，证实了该特定簇在调节Jun转录效力中的关键作用。
Like c-Fos, HBZ (HTLV-I bZIP factor) is able to interact with c-Jun but differs considerably from c-Fos in its ability to activate AP-1-responsive genes since HBZ rather inhibits transcriptional activity of c-Jun. To better understand the molecular mechanisms involved in this down-regulation of c-Jun activity, a large number of HBZ/c-Fos chimeras was constructed and analyzed for their ability to interact with c-Jun, to bind to the AP-1 motif and to stimulate expression of a reporter gene containing the collagenase promoter. By this approach, we demonstrate that the DNA-binding domain of HBZ is responsible for its inhibitory effect on the trans-activation potential of c-Jun. However, unexpectedly, we found that exchange of a cluster of six charged amino acids immediately adjacent to the DNA contact region altered significantly transcriptional activity of chimeras. This particular subdomain could be involved in efficient presentation of the AP-1 complex to the transcriptional machinery. To confirm this role, specific residues present in the cluster of HBZ were substituted for corresponding amino acids in c-Fos. Unlike the JunD-activating potential of wild-type HBZ, this mutant was no longer able to stimulate JunD activity, confirming the key role of this particular cluster in regulation of Jun transcriptional potency.