Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Cells. 2013 Aug;36(2):151-7. doi: 10.1007/s10059-013-0121-y. Epub 2013 Aug 1.
Under hypoxic conditions, cells activate a transcriptional response mainly driven by hypoxia-inducible factors (HIFs). HIF-1α stabilization and activity are known to be regulated by thioredoxin 1 (Txn1), but how the thioredoxin system regulates the hypoxic response is unknown. By examining the effects of Txn1 overexpression on HIF-1α function in HeLa, HT-29, MCF-7 and EMT6 cell lines, we found that this oxidoreductase did not stabilize HIF-1α, yet could increase its activity. These effects were dependent on the redox function of Txn1. However, Txn1 deficiency did not affect HIF-1α hypoxic-stabilization and activity, and overexpression of thioredoxin reductase 1 (TR1), the natural Txn1 reductase, had no influence on HIF-1α activity. Moreover, overexpression of Txn1 in TR1 deficient HeLa and EMT6 cells was still able to increase HIF-1α hypoxic activity. These results indicate that Txn1 is not essential for HIF-1α hypoxic stabilization or activity, that its overexpression can increase HIF-1α hypoxic activity, and that this effect is observed regardless of TR1 status. Thus, regulation of HIF-1α by the thioredoxin system depends on the specific levels of this system's major components.
在缺氧条件下，细胞主要通过缺氧诱导因子（HIFs）激活转录反应。众所周知，硫氧还蛋白 1（Txn1）可调节 HIF-1α的稳定性和活性，但硫氧还系统如何调节缺氧反应尚不清楚。通过研究 Txn1 过表达对 HeLa、HT-29、MCF-7 和 EMT6 细胞系中 HIF-1α功能的影响，我们发现这种氧化还原酶不能稳定 HIF-1α，但可以增加其活性。这些作用依赖于 Txn1 的氧化还原功能。然而，Txn1 缺乏并不影响 HIF-1α的缺氧稳定性和活性，天然 Txn1 还原酶硫氧还蛋白还原酶 1（TR1）的过表达对 HIF-1α活性也没有影响。此外，TR1 缺陷的 HeLa 和 EMT6 细胞中 Txn1 的过表达仍能增加 HIF-1α的缺氧活性。这些结果表明，Txn1 对于 HIF-1α 的缺氧稳定性或活性不是必需的，其过表达可以增加 HIF-1α 的缺氧活性，并且无论 TR1 状态如何，都可以观察到这种作用。因此，硫氧还系统对 HIF-1α 的调节取决于该系统主要成分的特定水平。
