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首页> 外文期刊>Biochemistry >Genetic evidence that stress-activated p38 MAP kinase is necessary but not sufficient for UV activation of HIV gene expression.
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Genetic evidence that stress-activated p38 MAP kinase is necessary but not sufficient for UV activation of HIV gene expression.

机译：遗传证据表明，压力激活的p38 MAP激酶对于UV激活HIV基因表达是必需的，但不足。

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We have examined the role of stress-activated p38 MAP kinase in regulating human immunodeficiency virus (HIV) gene expression in response to ultraviolet light (UV). We found that UV activated p38 in HeLa cells harboring stably integrated copies of an HIVcat plasmid to levels similar to those obtained by hyperosmotic shock. However, hyperosmotic shock resulted in one order of magnitude smaller increase in CAT activity than treatment with UV. The specific p38 inhibitor SB203580 significantly decreased (>80%) UV activation of HIV gene expression whereas PD98059, a specific MEK-1 inhibitor did not, suggesting that p38 is specifically involved in the HIV UV response and little to no contribution is provided by MEK-1 and the p42/p44 MAP kinase pathway. Whereas increased binding of NF-kappaB to an oligonucleotide spanning the HIV enhancer was observed after UV, as expected, this binding was not affected by SB203580. Furthermore, UV activation of HIV gene expression in cells having the cat reporter gene under control of an HIV promoter deleted of the enhancer (-69/+80) produced results indistinguishable from those using HIVcat/HeLa cells with an intact HIV promoter (-485/+80), suggesting that SB203580 acts through the basal transcription machinery. Northern blot analysis of steady-state RNA from HIVcat/HeLa cells revealed an almost complete inhibition of UV activation with SB203580 at the RNA level. Similarly, the UV response was almost completely obliterated at the CAT and RNA levels in HIVcat/HeLa cells stably transfected with a plasmid expressing a kinase-inactive mutant of p38 (isoform alpha), without affecting NF-kappaB activation, providing strong genetic evidence that p38, at least the alpha isoform, is necessary for UV activation of HIV gene expression and that NF-kappaB activation alone is insufficient. These results firmly establish p38 MAP kinase as a key modulator of HIV gene expression in response to UV that acts independently of NF-kappaB.
机译：我们已经检查了应激激活的p38 MAP激酶在调节人类免疫缺陷病毒（HIV）基因表达对紫外线（UV）的反应中的作用。我们发现，UV激活的HeLa细胞中的p38带有稳定整合的HIVcat质粒拷贝，其水平与高渗休克所获得的水平相似。但是，高渗休克导致CAT活性的增加比紫外线治疗小一个数量级。特异性p38抑制剂SB203580显着降低了HIV基因表达的紫外线激活（> 80％），而特异性MEK-1抑制剂PD98059却没有，这表明p38专门参与了HIV紫外线反应，而MEK几乎没有贡献。 -1和p42 / p44 MAP激酶途径。如预期的那样，在紫外线后观察到NF-κB与跨越HIV增强子的寡核苷酸的结合增加，该结合不受SB203580的影响。此外，在猫报告基因受增强子（-69 / + 80）缺失的HIV启动子控制下，猫报告基因的细胞中UV基因表达的紫外线活化产生的结果与使用带有完整HIV启动子的HIVcat / HeLa细胞的细胞没有区别（-485） / + 80），表明SB203580通过基础转录机制发挥作用。来自HIVcat / HeLa细胞的稳态RNA的Northern印迹分析表明，SB203580在RNA水平几乎完全抑制了UV活化。同样，在用表达p38激酶失活突变体（同种型α）的质粒稳定转染的HIVcat / HeLa细胞中，CAT和RNA水平上的紫外线反应几乎完全消失，而不会影响NF-κB的活化，提供了有力的遗传证据p38，至少是α同工型，对于UV激活HIV基因表达是必需的，仅NF-κB激活是不够的。这些结果牢固地将p38 MAP激酶确立为HIV基因表达的关键调节剂，以响应独立于NF-κB的紫外线。

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