Abstract
Few p53 regulators participate in selective control of p53-mediated cellular metabolism. How p53-mediated aerobic and glycolytic pathways are negatively regulated remains largely unclear. Here, we identified two KRAB-type zinc-finger proteins, PITA (p53 inhibitor of TIGAR activation) and PISA (p53 inhibitor of SCO2 activation), as selective regulators of p53 in metabolic control. PITA and PISA interact with p53 and specifically suppress transcription of the glycolysis regulator TIGAR and the oxidation phosphorylation regulator SCO2, respectively. Importantly, PITA transgenic mice exhibited increased 6-phosphofructokinase 1 (PFK1) activity and an elevated glycolytic rate, whereas PISA transgenic mice had decreased cytochrome c oxidase activity and reduced mitochondrial respiration. In response to glucose starvation, PITA dissociates from p53, resulting in activation of p53 and induction of TIGAR, which inhibited aerobic glycolysis. Prolonged starvation leads to PISA dissociation from p53 and induction of SCO2 and p53-promoted mitochondrial respiration. The dynamic regulation of PITA and PISA upon metabolic stress is dependent on ATM kinase-mediated phosphorylation of PITA and PISA. Furthermore, in human colorectal cancers, the elevated expression of PITA and PISA correlates with cancer progression. Depletion of PITA or PISA in colorectal cancer cells reduced the cell proliferation, migration and invasion. These results identify PITA and PISA as selective regulators of p53-mediated glycolysis and mitochondrial respiration and provide novel insights into the role of p53 network in cell metabolic control.
Highlights
The tumor suppressor p53 plays an important role in controlling of cell cycle arrest, DNA repair and apoptosis
The p533KR mutant retains the capacity to inhibit glycolysis and reduce reactive oxygen species (ROS) levels. These results suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are crucial to the suppression of early onset spontaneous tumorigenesis.[1, 2] p53 has a role in modulating metabolism, including glycolysis and oxidative phosphorylation (OXPHOS),[3] and can prevent metabolic transformation by restraining the glycolytic pathway
Coexpression of PITA with p53 reduced the occupancy of p53 at the intron of TIGAR, and co-expression of PISA with p53 reduced the occupancy of p53 at the intron of SCO2 (Fig. 2b). These data suggest a model in which PITA or PISA binds to p53 and selectively interferes with its binding to aerobic glycolysis and mitochondrial respiration targets, that is to say TIGAR and SCO2, respectively
Summary
The tumor suppressor p53 plays an important role in controlling of cell cycle arrest, DNA repair and apoptosis. Emerging data are revealing that regulation of energy metabolism and the Warburg effect is a novel function of p53 in tumor suppression.[1] Interestingly, tumor suppression can be mediated by a p53 polypeptide (e.g. p533KR) that lacks the ability to induce p53-dependent cell cycle arrest, apoptosis and senescence. These results indicate that other p53 functions are sufficient to suppress tumor formation.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
