AMPK couples p73 with p53 in cell fate decision

Abstract

The p53 family of proteins has an important role in determining cell fate in response to different types of stress, such as DNA damage, hypoxia, or oncogenic stress. In recent years, p53 has also been shown to respond to metabolic stress, and to be induced by the AMP-activated protein kinase (AMPK), a central cellular energy sensor. A bioinformatic analysis revealed three putative AMPK phopshorylation sites in p73, a p53 tumor suppressor paralog. In vitro and in vivo assays confirmed that AMPK phosphorylates p73 on a novel residue, S426. Following specific pharmacologic stimulation of AMPK in cells, p73 protein halflife was prolonged leading to p73 accumulation in the nucleus. We show that p73 escaped the E3 ligase Itch resulting in reduced p73 ubiquitination and proteasomal degradation. Furthermore, chronic activation of AMPK led to apoptosis that was p73 dependent, but only in p53-expressing cells. Surprisingly, we found that p73 was required for p53 stabilization and accumulation under AMPK activation, but was dispensable under DNA damage. Our findings couple p73 with p53 in determining cell fate under AMPK-induced metabolic stress.

A balancing act: orchestrating amino-truncated and full-length p73 variants as decisive factors in cancer progression

“…58,163 Pharmacological stimulation of AMP-activated protein kinase leads to accumulation of TAp73 in the nucleus via direct phosphorylation and causes apoptosis, however, only in the presence of p53. 164 Smallmolecule inhibitors of phosphatidylinositol 3′-kinase, AKT or prodigiosin disrupt the inhibitory effect of mutant p53 on TAp73. 165,166 T-oligos trigger inherent telomere-based DNAdamage responses and engage TAp73 in p53-deficient melanoma cells.…”

P63 in health and cancer

“…TAp73 is essential for p53 stabilization during AMPK activation. Yet, TAp73 is dispensable for p53 activation following DNA damage (Adamovich et al, 2014). A recent study shows that TAp63 controls various aspects of metabolism.…”

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…Metabolic regulation by p53 family appears a key function for their cancer-related but also ageing-related phenotype. All the three members promote mitochondrial respiration thought regulation of different metabolic enzymes, including the glutaminase 2 (Gls2) (Adamovich et al, 2014;Amelio et al, 2014b;Bellomaria et al, 2010Bellomaria et al, , 2012Giacobbe et al, 2013;He et al, 2013;Hu et al, 2010;Sharif et al, 2015;Simon et al, 2014;Velletri et al, 2013;Viticchie et al, 2015). Gls2 regulates glutamine utilization, supplying anaplerotic flux of substrates resulting in promotion of mitochondrial activity and ATP synthesis (Amelio et al, 2014a;Maniam et al, 2015).…”