Puma, noxa, p53, and p63 differentially mediate stress pathway induced apoptosis

Wang, J., Thomas, H.R., Li, Z., Yeo, N.C.F., Scott, H.E., Dang, N., Hossain, M.I., Andrabi, S.A., Parant, J.M.
Cell Death & Disease   12: 659 (Journal)
Registered Authors
Parant, John, Thomas, Holly R.
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Apoptosis*/drug effects
  • Apoptosis*/radiation effects
  • Apoptosis Regulatory Proteins/genetics
  • Apoptosis Regulatory Proteins/metabolism*
  • DNA Damage*
  • Endoplasmic Reticulum Stress*/drug effects
  • Gene Expression Regulation
  • Macrolides/pharmacology
  • Oxidative Stress*/drug effects
  • Phosphoproteins/genetics
  • Phosphoproteins/metabolism*
  • Proto-Oncogene Proteins/genetics
  • Proto-Oncogene Proteins/metabolism*
  • Proto-Oncogene Proteins c-bcl-2/genetics
  • Proto-Oncogene Proteins c-bcl-2/metabolism*
  • Proto-Oncogene Proteins c-mdm2/genetics
  • Proto-Oncogene Proteins c-mdm2/metabolism
  • Signal Transduction
  • Tetradecanoylphorbol Acetate/pharmacology
  • Thapsigargin/pharmacology
  • Time Factors
  • Trans-Activators/genetics
  • Trans-Activators/metabolism*
  • Transcription, Genetic
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism*
  • X-Rays
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
34193827 Full text @ Cell Death Dis.
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.
Genes / Markers
Figure Gallery
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes