Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 22, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2123202119
Keywords
p53 family; p73; p73 C-terminal isoforms; Notch1 pathway; tumor suppressor
Categories
Funding
- National Institutes of Health [CA081237, CA224433]
- UC Davis Cancer Center Core Support [CA093373]
- TRDRP [T31IP1727]
- [T32 HL007013]
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p73 alpha 1 plays a critical role in tumor suppression and the inflammatory response via regulation of Notch1.
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 p73 alpha to isoform p73 alpha 1. We found that p73 alpha 1 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 p73 alpha 1 suppresses cell proliferation, whereas knockdown of p73 alpha 1 restores the cell proliferative and migratory capacities of E12(-/-) cells. Consistently, we found that E/2(+/-) mice are not prone to spontaneous tumors. Instead, E12(+/-) mice are prone to systemic inflammation and exhibit elevated TNF alpha expression in inflamed tissues. Moreover, we found that Notch1, a master regulator of the inflammatory response, is regulated by p73 alpha 1 and highly expressed in E12(-)(/-) cells and inflamed E12(+/-) mouse tissues. Furthermore, through knockdown of p73 alpha 1 and/or Notch1 in E12(-/-) cells, we found that Notch1 is necessary for p73 alpha 1-mediated growth suppression. Together, these data suggest that p73 alpha 1 plays a critical role in tumor suppression and the inflammatory response via Notch1.
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