LAUSR

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 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-1α 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.Selective signalling stimulates tumour vascularisationThe stabilisation of an important signalling protein can fuel tumour growth and progression—but only under the right environmental conditions. Paradoxically, the TAp73 protein can both suppress tumorigenesis and stimulate formation of tumour-feeding blood vessels. The latter effect appears to be linked with exposure to oxygen-poor conditions within solid tumours, and researchers led by Kanaga Sabapathy at Singapore’s National Cancer Centre recently explored the mechanisms regulating TAp73 activity. Sabapathy’s team showed that the action of a protein called AMPK helps to prevent TAp73 from being degraded. However, activation of AMPK in isolation is insufficient to promote TAp73-mediated blood vessel growth. Instead, the researchers only observed this effect when AMPK was specifically activated due to oxygen deprivation, revealing the existence of multiple TAp73-regulating pathways that could explain this protein’s seemingly contradictory effects on cell growth.