PUBLICATION

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

Authors

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.

ID

ZDB-PUB-210702-5

Date

2021

Source

Cell Death & Disease 12: 659 (Journal)

Registered Authors

Parant, John, Thomas, Holly R.

Keywords

none

MeSH Terms

Tumor Suppressor Protein p53/genetics
Tumor Suppressor Protein p53/metabolism*
Phosphoproteins/genetics
Phosphoproteins/metabolism*
Proto-Oncogene Proteins c-bcl-2/genetics
Proto-Oncogene Proteins c-bcl-2/metabolism*
Animals, Genetically Modified
Proto-Oncogene Proteins c-mdm2/genetics
Proto-Oncogene Proteins c-mdm2/metabolism
Endoplasmic Reticulum Stress*/drug effects
Gene Expression Regulation
Tetradecanoylphorbol Acetate/pharmacology
Time Factors
Transcription, Genetic
Apoptosis Regulatory Proteins/genetics
Apoptosis Regulatory Proteins/metabolism*
Signal Transduction
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Oxidative Stress*/drug effects
Apoptosis*/drug effects
Apoptosis*/radiation effects
Proto-Oncogene Proteins/genetics
Proto-Oncogene Proteins/metabolism*
Thapsigargin/pharmacology
Animals
DNA Damage*
X-Rays
Zebrafish/genetics
Trans-Activators/genetics
Trans-Activators/metabolism*
Macrolides/pharmacology

(all 32)

PubMed

34193827 Full text @ Cell Death Dis.

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.

Genes / Markers

Figures

Show all Figures

Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
mdm2^uab9/uab9	standard conditions	10-13 somites	whole organism	RTPCR	Fig. 4
tp53^uab6/uab6	x-ray	Prim-5	whole organism	RTPCR	Fig. 3
tp53^uab6/uab6	standard conditions	Prim-5	whole organism	RTPCR	Fig. 3
WT	chemical treatment by environment: thapsigargin	Prim-5	whole organism	RTPCR	Fig. 1
WT	chemical treatment by environment: phorbol 13-acetate 12-myristate	Prim-5	whole organism	RTPCR	Fig. 1
WT	x-ray	Prim-5	whole organism	RTPCR	Fig. 1
WT	standard conditions	10-13 somites	whole organism	RTPCR	Fig. 4
WT	chemical treatment by environment: phorbol 13-acetate 12-myristate	Prim-5	whole organism	RTPCR	Fig. 7
WT	standard conditions	Prim-5	whole organism	RTPCR	Fig. 3
WT	standard conditions	Prim-5	whole organism	RTPCR	Fig. 7

1 - 10 of 40

Show

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: phorbol 13-acetate 12-myristate	Prim-5	whole organism bbc3 expression increased amount, abnormal	Fig. 1
WT	chemical treatment by environment: phorbol 13-acetate 12-myristate	Prim-5	whole organism bbc3 expression increased amount, abnormal	Fig. 7
WT	chemical treatment by environment: phorbol 13-acetate 12-myristate	Prim-5	whole organism pmaip1 expression increased amount, abnormal	Fig. 1
WT	chemical treatment by environment: phorbol 13-acetate 12-myristate	Prim-5	whole organism pmaip1 expression increased amount, abnormal	Fig. 7
WT	chemical treatment by environment: phorbol 13-acetate 12-myristate	Prim-5	whole organism apoptotic process increased occurrence, abnormal	Fig. 7
WT	chemical treatment by environment: thapsigargin	Prim-5	whole organism bbc3 expression increased amount, abnormal	Fig. 5
WT	chemical treatment by environment: thapsigargin	Prim-5	whole organism bbc3 expression increased amount, abnormal	Fig. 1
WT	chemical treatment by environment: thapsigargin	Prim-5	whole organism bida expression decreased amount, abnormal	Fig. 1
WT	chemical treatment by environment: thapsigargin	Prim-5	whole organism pmaip1 expression increased amount, abnormal	Fig. 5
WT	chemical treatment by environment: thapsigargin	Prim-5	whole organism pmaip1 expression increased amount, abnormal	Fig. 1

1 - 10 of 51

Show

Mutations / Transgenics

Allele	Type	Affected Genomic Region
uab4	Small Deletion	bbc3
uab5	Indel	pmaip1
uab6	Insertion	tp53
uab7	Insertion	tp63
uab8	Small Deletion	tp73
uab9	Small Deletion	mdm2

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
bbc3	TALEN2-bbc3	TALEN
mdm2	TALEN2-mdm2	TALEN
pmaip1	TALEN2-pmaip1	TALEN
tp53	CRISPR13-tp53	CRISPR
tp73	CRISPR1-tp73	CRISPR

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Wang et al., 2021 ZDB-PUB-210702-5 PMID:34193827

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

Wang et al., 2021

ZDB-PUB-210702-5
PMID:34193827