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首页> 外文期刊>Molecular and Cellular Biology >DNA Damage Is a Prerequisite for p53-Mediated Proteasomal Degradation of HIF-1α in Hypoxic Cells and Downregulation of the Hypoxia Marker Carbonic Anhydrase IX
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DNA Damage Is a Prerequisite for p53-Mediated Proteasomal Degradation of HIF-1α in Hypoxic Cells and Downregulation of the Hypoxia Marker Carbonic Anhydrase IX

机译：DNA损伤是缺氧细胞中p53介导的HIF-1α蛋白酶体降解和缺氧标记碳酸酐酶IX下调的前提条件

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摘要

We investigated the relationship between the tumor suppressor p53 and the hypoxia-inducible factor-1 (HIF-1)-dependent expression of the hypoxia marker, carbonic anhydrase IX (CAIX). MCF-7 (wt p53) and Saos-2 (p53-null) cells displayed similar induction of CAIX expression and CA9 promoter activity under hypoxic conditions. Activation of p53 by the DNA damaging agent mitomycin C (MC) was accompanied by a potent repression of CAIX expression and the CA9 promoter in MCF-7 but not in Saos-2 cells. The activated p53 mediated increased proteasomal degradation of HIF-1α protein, resulting in considerably lower steady-state levels of HIF-1α protein in hypoxic MCF-7 cells but not in Saos-2 cells. Overexpression of HIF-1α relieved the MC-induced repression in MCF-7 cells, confirming regulation at the HIF-1α level. Similarly, CA9 promoter activity was downregulated by MC in HCT 116 p53+/+ but not the isogenic p53?/? cells. Activated p53 decreased HIF-1α protein levels by accelerated proteasome-dependent degradation without affecting significantly HIF-1α transcription. In summary, our results demonstrate that the presence of wtp53 under hypoxic conditions has an insignificant effect on the stabilization of HIF-1α protein and HIF-1-dependent expression of CAIX. However, upon activation by DNA damage, wt p53 mediates an accelerated degradation of HIF-1α protein, resulting in reduced activation of CA9 transcription and, correspondingly, decreased levels of CAIX protein. A model outlining the quantitative relationship between p53, HIF-1α, and CAIX is presented.
机译：我们研究了肿瘤抑制因子p53与缺氧标记物碳酸酐酶IX（CAIX）的低氧诱导因子-1（HIF-1）依赖性表达之间的关系。在缺氧条件下，MCF-7（wt p53）和Saos-2（p53-null）细胞显示出相似的CAIX表达诱导和 CA9 启动子活性。 DNA破坏剂丝裂霉素C（MC）对p53的激活伴随着MCF-7中CAIX表达和 CA9 启动子的有效抑制，而Saos-2细胞则没有。活化的p53介导的HIF-1α蛋白的蛋白酶体降解增加，导致低氧MCF-7细胞中Saif-2细胞中HIF-1α蛋白的稳态水平大大降低。 HIF-1α的过表达缓解了MCF-7细胞中MC诱导的阻遏，证实了在HIF-1α水平的调控。相似地，MC9在HCT 116 p53 + / + 细胞中下调了 CA9 启动子活性，但同基因p53 ？/？细胞中却没有。活化的p53通过促进蛋白酶体依赖性降解降低HIF-1α蛋白水平，而不会显着影响HIF-1α转录。总之，我们的结果表明在低氧条件下wtp53的存在对CAIF的HIF-1α蛋白和HIF-1依赖性表达的稳定作用不显着。然而，通过DNA损伤激活后，wt p53介导了HIF-1α蛋白的加速降解，导致 CA9 转录的激活减少，相应地，CAIX蛋白的水平降低。提出了一个模型，概述了p53，HIF-1α和CAIX之间的定量关系。

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