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|Title:||Context-dependent AMPK activation distinctly regulates TAp73 stability and transcriptional activity||Authors:||Li, D.
|Issue Date:||2018||Publisher:||Springer Nature||Citation:||Li, D., Dulloo, I., Sabapathy, K. (2018). Context-dependent AMPK activation distinctly regulates TAp73 stability and transcriptional activity. Signal Transduction and Targeted Therapy 3 (1) : 20. ScholarBank@NUS Repository. https://doi.org/10.1038/s41392-018-0020-y||Rights:||Attribution 4.0 International||Abstract:||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-1?-mediated repression of the E3 ligase Siah1. Elevated TAp73 in turn regulates the angiogenic transcriptional programme, exemplified by vegf-A 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-1? activation, and transcriptional repression of Siah1. Furthermore, while vegf-A up-regulation upon hypoxia requires AMPK, direct activation of AMPK by AICAR does not activate vegf-A. 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. © 2018, The Author(s).||Source Title:||Signal Transduction and Targeted Therapy||URI:||https://scholarbank.nus.edu.sg/handle/10635/212375||ISSN:||20959907||DOI:||10.1038/s41392-018-0020-y||Rights:||Attribution 4.0 International|
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