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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p73α1, a p73 C-terminal isoform, regulates tumor suppression and the inflammatory response via Notch1
Kyra Nicole Laubach1, Wensheng Yan1, Xiangmudong Kong1
1Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA 95616.
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.
Insights
The p73α1 isoform, induced by DNA damage, suppresses tumor growth and promotes inflammation via Notch1 signaling. Its knockout impacts cell proliferation and senescence, highlighting its critical role in cancer and immunity.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- The p53 family member p73 exhibits alternative splicing, producing various isoforms with largely unknown expression and activity.
- Understanding p73 isoform function is crucial for cancer and inflammatory disease research.
Purpose of the Study:
- To investigate the role of p73 isoforms, specifically focusing on the impact of exon 12 (E12) knockout on p73α1 expression and function.
- To elucidate the involvement of p73α1 in tumor suppression, cell growth, migration, senescence, and inflammatory responses.
Main Methods:
- CRISPR-Cas9 gene editing was employed to knock out exon 12 (E12) in human cancer cell lines (H1299, MIA PaCa-2) and mice.
- Cell proliferation, migration, and senescence assays were performed.
- Tumorigenesis and inflammatory responses in E12 knockout mice were analyzed.
- Expression levels of p73α1, TNFα, and Notch1 were assessed.
Main Results:
- Exon 12 knockout led to an isoform switch from p73α to p73α1, which is naturally expressed and induced by DNA damage.
- p73α1 expression suppressed cell growth, migration, and promoted senescence.
- E12 knockout mice exhibited systemic inflammation with elevated TNFα and Notch1 expression.
- Notch1 was identified as necessary for p73α1-mediated growth suppression.
Conclusions:
- p73α1 plays a significant role in tumor suppression by inhibiting cell proliferation and migration.
- p73α1 is involved in regulating the inflammatory response, partly through Notch1 signaling.
- The p73α1 isoform is a critical mediator in both cancer development and immune system regulation.
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