Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore.
Sir William Dunn School of Pathology, University of Oxford, South Parks Road Oxford, Oxford, OX1 3RE, UK.
Signal Transduct Target Ther. 2018 Jul 27;3:20. doi: 10.1038/s41392-018-0020-y. eCollection 2018.
TAp73, the homologue of the tumour suppressor p53, has dual roles in tumourigenesis: both as a tumour suppressor and as a promoter of tumour growth. We have recently shown that hypoxia, a condition prevalent in tumours, results in the stabilisation of TAp73 through a mechanism involving HIF-1α-mediated repression of the E3 ligase . Elevated TAp73 in turn regulates the angiogenic transcriptional programme, exemplified by activation, thereby promoting angiogenesis and tumour growth. To further understand hypoxia-mediated TAp73 regulation, we have focused on the Adenosine monophosphate (AMP)-dependent protein kinase (AMPK) signalling pathway induced by hypoxia. We show that hypoxia-mediated AMPK activation is required for efficient TAp73 stabilisation, through multiple means by using AMPK-deficient cells or inhibiting its activity and expression. Conversely, direct AMPK activation using its activator AICAR is also sufficient to induce TAp73 stabilisation but this is independent of putative AMPK phosphorylation sites on TAp73, HIF-1α activation, and transcriptional repression of . Furthermore, while up-regulation upon hypoxia requires AMPK, direct activation of AMPK by AICAR does not activate . Consistently, supernatant from cells exposed to hypoxia, but not AICAR, was able to induce tube formation in HUVECs. These data therefore highlight that the processes of TAp73 stabilisation and transcriptional activation of angiogenic target genes by AMPK activation can be decoupled. Collectively, these results suggest that the context of AMPK activation determines the effect on TAp73, and proposes a model in which hypoxia-induced TAp73 stabilisation occurs by parallel pathways converging to mediate its transactivation potential.
TAp73 是肿瘤抑制因子 p53 的同源物，在肿瘤发生中具有双重作用：既是肿瘤抑制因子，也是肿瘤生长的促进剂。我们最近表明，缺氧是肿瘤中普遍存在的一种情况，通过一种涉及 HIF-1α 介导的 E3 连接酶抑制的机制，导致 TAp73 稳定。升高的 TAp73 反过来又调节血管生成转录程序，以 激活为代表，从而促进血管生成和肿瘤生长。为了进一步了解缺氧介导的 TAp73 调节，我们专注于缺氧诱导的腺苷一磷酸（AMP）依赖性蛋白激酶（AMPK）信号通路。我们表明，缺氧介导的 AMPK 激活是 TAp73 稳定所必需的，通过使用 AMPK 缺陷细胞或抑制其活性和表达的多种方式。相反，使用其激活剂 AICAR 直接激活 AMPK 也足以诱导 TAp73 稳定，但这独立于 TAp73 上假定的 AMPK 磷酸化位点、HIF-1α 激活和 的转录抑制。此外，虽然 在上调需要 AMPK，但 AICAR 直接激活 AMPK 不会激活 。一致地，来自暴露于缺氧但不是 AICAR 的细胞的上清液能够诱导 HUVECs 形成管腔。因此，这些数据突出表明，TAp73 稳定和血管生成靶基因的转录激活过程可以通过 AMPK 激活解耦。总的来说，这些结果表明 AMPK 激活的情况决定了对 TAp73 的影响，并提出了一个模型，其中缺氧诱导的 TAp73 稳定通过平行途径发生，这些途径汇聚以介导其转录激活潜力。
