p73α1, a p73 C-terminal isoform, regulates tumor suppression and the inflammatory response via Notch1

Significance

p73 is expressed as multiple C-terminal isoforms, but their expression and activity are largely unknown. Here, we identified p73α1 as a p73 C-terminal isoform that results from exon 12 ( E12) exclusion. We showed that E12 deficiency in mice leads to systemic inflammation but not spontaneous tumors. We also showed that Notch1 is regulated by p73α1 and plays a critical role in p73-dependent tumor suppression and systemic inflammation.

Abstract

p73, a p53 family member, undergoes alternative splicing at the 3′ end to produce multiple isoforms, but their expression and activity are largely unknown. Thus, CRISPR was used to knock out exon 12 ( E12) in human cancer cell lines and mice, leading to isoform switch from p73α to isoform p73α1. We found that p73α1 is naturally expressed and induced by DNA damage. We also found that knockout of E12 suppresses cell growth and migration in H1299 and MIA PaCa-2 cells and promotes cellular senescence in mouse embryonic fibroblasts. Similarly, ectopic expression of p73α1 suppresses cell proliferation, whereas knockdown of p73α1 restores the cell proliferative and migratory capacities of E12 ^−/− cells. Consistently, we found that E12 ^+/− mice are not prone to spontaneous tumors. Instead, E12 ^+/− mice are prone to systemic inflammation and exhibit elevated TNFα expression in inflamed tissues. Moreover, we found that Notch1, a master regulator of the inflammatory response, is regulated by p73α1 and highly expressed in E12 ^−/− cells and inflamed E12 ^+/− mouse tissues. Furthermore, through knockdown of p73α1 and/or Notch1 in E12 ^−/− cells, we found that Notch1 is necessary for p73α1-mediated growth suppression. Together, these data suggest that p73α1 plays a critical role in tumor suppression and the inflammatory response via Notch1.