TY - JOUR
T1 - p73α1, a p73 C-terminal isoform, regulates tumor suppression and the inflammatory response via Notch1
AU - Laubach, Kyra Nicole
AU - Yan, Wensheng
AU - Kong, Xiangmudong
AU - Sun, Wenqiang
AU - Chen, Mingyi
AU - Zhang, Jin
AU - Chen, Xinbin
N1 - Publisher Copyright:
Copyright © 2022 the Author(s).
PY - 2022/5/31
Y1 - 2022/5/31
N2 - p73, a p53 family member, undergoes alternative splicing at the 30 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 E122/2 cells. Consistently, we found that E12+/2 mice are not prone to spontaneous tumors. Instead, E12+/2 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 E122/2 cells and inflamed E12+/2 mouse tissues. Furthermore, through knockdown of p73α1 and/or Notch1 in E122/2 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.
AB - p73, a p53 family member, undergoes alternative splicing at the 30 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 E122/2 cells. Consistently, we found that E12+/2 mice are not prone to spontaneous tumors. Instead, E12+/2 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 E122/2 cells and inflamed E12+/2 mouse tissues. Furthermore, through knockdown of p73α1 and/or Notch1 in E122/2 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.
KW - Notch1 pathway
KW - p53 family
KW - p73
KW - p73 C-terminal isoforms
KW - tumor suppressor
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U2 - 10.1073/pnas.2123202119
DO - 10.1073/pnas.2123202119
M3 - Article
C2 - 35617425
AN - SCOPUS:85130902808
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 22
M1 - e2123202119
ER -