| First Author | Zhang J | Year | 2023 |
| Journal | Cell Death Dis | Volume | 14 |
| Issue | 1 | Pages | 14 |
| PubMed ID | 36631448 | Mgi Jnum | J:332505 |
| Mgi Id | MGI:7426249 | Doi | 10.1038/s41419-022-05529-7 |
| Citation | Zhang J, et al. (2023) TP73 Isoform-specific disruption reveals a critical role of TAp73beta in growth suppression and inflammatory response. Cell Death Dis 14(1):14 |
| abstractText | TP73 is expressed as multiple N- and C-terminal isoforms through two separate promoters or alternative splicing. While N-terminal p73 isoforms have been well studied, very little is known about p73 C-terminal isoforms. Thus, CRISPR was used to delete TP73 Exon13 (E13-KO) to induce p73alpha to p73beta isoform switch. We showed that E13-KO led to decreased cell proliferation and migration and sensitized cells to ferroptosis, which can be reverted by knockdown of TAp73beta in E13-KO cells. To understand the biological function of p73beta in vivo, we generated a mouse model in that the Trp73 E13 was deleted by CRISPR. We showed that p73alpha to p73beta isoform switch led to increased cellular senescence in mouse embryonic fibroblasts. We also showed that E13-deficient mice exhibited shorter life span and were prone to spontaneous tumors, chronic inflammation and liver steatosis as compared to WT mice. Additionally, we found that the incidence of chronic inflammation and liver steatosis was higher in E13-deficient mice than that in Trp73-deficient mice, suggesting that p73beta is a strong inducer of inflammatory response. Mechanistically, we showed that TAp73beta was able to induce cysteine dioxygenase 1 (CDO-1), leading to cysteine depletion and subsequently, enhanced ferroptosis and growth suppression. Conversely, knockdown of CDO-1 was able to alleviate the growth suppression and ferroptosis in E13-KO cells. Together, our data suggest that at a physiologically relevant level, TAp73beta is a strong inducer of growth suppression but insufficient to compensate for loss of TAp73alpha in tumor suppression due to aberrant induction of inflammatory response and liver steatosis. |
