Puma, noxa, p53, and p63 differentially mediate stress pathway induced apoptosis
Open Access
- 30 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (7), 1-11
- https://doi.org/10.1038/s41419-021-03902-6
Abstract
Cellular stress can lead to several human disease pathologies due to aberrant cell death. The p53 family (tp53, tp63, and tp73) and downstream transcriptional apoptotic target genes (PUMA/BBC3 and NOXA/PMAIP1) have been implicated as mediators of stress signals. To evaluate the importance of key stress response components in vivo, we have generated zebrafish null alleles in puma, noxa, p53, p63, and p73. Utilizing these genetic mutants, we have deciphered that the apoptotic response to genotoxic stress requires p53 and puma, but not p63, p73, or noxa. We also identified a delayed secondary wave of genotoxic stress-induced apoptosis that is p53/puma independent. Contrary to genotoxic stress, ER stress-induced apoptosis requires p63 and puma, but not p53, p73, or noxa. Lastly, the oxidative stress-induced apoptotic response requires p63, and both noxa and puma. Our data also indicate that while the neural tube is poised for apoptosis due to genotoxic stress, the epidermis is poised for apoptosis due to ER and oxidative stress. These data indicate there are convergent as well as unique molecular pathways involved in the different stress responses. The commonality of puma in these stress pathways, and the lack of gross or tumorigenic phenotypes with puma loss suggest that a inhibitor of Puma may have therapeutic application. In addition, we have also generated a knockout of the negative regulator of p53, mdm2 to further evaluate the p53-induced apoptosis. Our data indicate that the p53 null allele completely rescues the mdm2 null lethality, while the puma null completely rescues the mdm2 null apoptosis but only partially rescues the phenotype. Indicating Puma is the key mediator of p53-dependent apoptosis. Interestingly the p53 homozygous null zebrafish develop tumors faster than the previously described p53 homozygous missense mutant zebrafish, suggesting the missense allele may be hypomorphic allele.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA216108)
This publication has 83 references indexed in Scilit:
- p63 Mediates an Apoptotic Response to Pharmacological and Disease-Related ER Stress in the Developing EpidermisDevelopmental Cell, 2011
- Physiological consequences of defects in ERCC1–XPF DNA repair endonucleaseDNA Repair, 2011
- Modeling Neurodegeneration in ZebrafishCurrent Neurology and Neuroscience Reports, 2011
- The DNA Damage Response: Making It Safe to Play with KnivesMolecular Cell, 2010
- Chk1 Suppresses a Caspase-2 Apoptotic Response to DNA Damage that Bypasses p53, Bcl-2, and Caspase-3Cell, 2008
- In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contributeCell Death & Differentiation, 2008
- Transparent Adult Zebrafish as a Tool for In Vivo Transplantation AnalysisCell Stem Cell, 2008
- p63 and p73 are required for p53-dependent apoptosis in response to DNA damageNature, 2002
- Regulation of p53 stability by Mdm2Nature, 1997
- Mdm2 promotes the rapid degradation of p53Nature, 1997