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

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.

Mechanisms of Cannabidiol (CBD) in Cancer Treatment: A Review

“…The cellular stress mediators, the p53 family, and their downstream transcriptional targets, such as PUMA and Noxa, play an important role during apoptosis. Cellular stress, including oxidative stress, DNA damage stress, and unfolded protein stress, typically lead to cell death and the clearance of stressed cells [ 66 ]. CHOP is involved in endoplasmic reticulum stress-induced apoptosis, in which the prolonged activation of unfolded endoplasmic reticulum proteins stimulates apoptotic cell death via the upregulation of CHOP [ 67 ].…”

A Novel ER Stress Mediator TMTC3 Promotes Squamous Cell Carcinoma Progression by Activating GRP78/PERK Signaling Pathway

“…3 D). Additionally, it was reported that TP63 has been implicated as a mediator of stress signals, including ER stress and oxidative stress 18 . The expression of ΔNp63 was activated by ER stress in zebrafish 19 .…”

Genomewide m6A mapping uncovers dynamic changes in the m6A epitranscriptome of cisplatin-treated apoptotic HeLa cells

“…We then investigated the association of individual mRNAs with actively translating polysomes. To this extent, we first fractionated the cytoplasmic extracts of HeLa cells into four major fractions (1) mRNP fraction composed primarily of non-translated ribonucleoproteins; (2) monosome constituting mRNAs associated with a single ribosome; (3) light polysome that contains mRNAs associated with up to 3 ribosomes; and (4) heavy polysome that contains mRNAs with more than 3 ribosomes. We performed qPCR analyses with total RNAs phenol extracted from each fraction.…”

“…Although miCLIP-seq is a highly sensitive approach to examine m 6 A-methylated transcripts genomewide, the potential for false positive sites that might arise from a cross-hybridization mandates validation of m 6 A sites of interest (16). Thus, we employed SELECT (18) to confirm differential m 6 A methylation on four mRNAs, namely PHLDA1, PIDD1, PMAIP1 and TRAP1, all of which have been reported to be key players in modulation of apoptosis [Table 1; (4,(22)(23)(24)]. To this extent, we first used the m 6 A site at the 2525 th adenosine nucleotide of MALAT1 as a positive control to ensure that this method properly detects m 6 A-methylated residues (18).…”

“…DNA lesions interfere with proper DNA replication and transcription, leading to the activation of DNA-damage response (DDR) and P53. P53 then transcriptionally coordinates the expression of genes that primarily triggers the intrinsic pathway of apoptosis as well as the extrinsic pathway (4). However, the efficacy of drugs plummets dramatically due to the drug resistance, which constitutes a major challenge in clinics for the proper treatment of cancer patients.…”