TLX controls angiogenesis through interaction with the von Hippel-Lindau protein.
TLX controls angiogenesis through interaction with the von Hippel-Lindau protein.
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DOI：
10.1242/bio.2012893
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发表时间：
2012-06-15
期刊：
影响因子：
2.4
通讯作者：
Funa K
中科院分区：
文献类型：
--
作者：
Zeng ZJ;Johansson E;Hayashi A;Chavali PL;Akrap N;Yoshida T;Kohno K;Izumi H;Funa K
TLX被认为是维持神经干细胞在成体神经发生中不可或缺的孤儿核受体。我们在这里报告说，神经母细胞瘤细胞系表达高水平的TLX，这进一步增加了缺氧，从而增强了这些细胞的血管生成能力。TLX的促血管生成活性似乎是由其与稳定TLX的von Hippel-Lindau蛋白（pVHL）的直接结合诱导的。反过来，TLX与羟化缺氧诱导因子（HIF-α）竞争结合pVHL，这有助于在常氧条件下稳定神经母细胞瘤中的HIF-2α。缺氧时，TLX在细胞核中增加，与VEGF启动子染色质上的HIF反应元件紧密结合，并与HIF-2α一起募集RNA聚合酶II以诱导VEGF表达。相反，通过shRNA去除TLX降低了HIF-2α和VEGF的表达，以及神经母细胞瘤细胞系IMR-32和SH-SY 5 Y的促生长和集落形成能力。相反，沉默HIF-2α将略微增加TLX，表明当HIF-2α降低时，TLX起到维持低氧环境的作用。我们的研究结果表明TLX通过调节HIF-2α在控制血管生成中起关键作用。TLX和pVHL可能在重要的命运决定中相互抵消，例如自我更新和分化，以及血管生成和抗血管生成。
TLX is known as the orphan nuclear receptor indispensable for maintaining neural stem cells in adult neurogenesis. We report here that neuroblastoma cell lines express high levels of TLX, which further increase in hypoxia to enhance the angiogenic capacity of these cells. The proangiogenetic activity of TLX appears to be induced by its direct binding to the von Hippel-Lindau protein (pVHL), which stabilizes TLX. In turn, TLX competes with hydroxylated hypoxia-inducible factor (HIF-α) for binding to pVHL, which contributes to the stabilization of HIF-2α in neuroblastoma during normoxia. Upon hypoxia, TLX increases in the nucleus where it binds in close proximity of the HIF-response element on the VEGF-promoter chromatin, and, together with HIF-2α, recruits RNA polymerase II to induce VEGF expression. Conversely, depletion of TLX by shRNA decreases the expression of HIF-2α and VEGF as well as the growth-promoting and colony-forming capacity of the neuroblastoma cell lines IMR-32 and SH-SY5Y. On the contrary, silencing HIF-2α will slightly increase TLX, suggesting that TLX acts to maintain a hypoxic environment when HIF-2α is decreasing. Our results demonstrate TLX to play a key role in controlling angiogenesis by regulating HIF-2α. TLX and pVHL might counterbalance each other in important fate decisions such as self-renewal and differentiation, as well as angiogenesis and anti-angiogenesis.
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