The function of Drosophila p53 isoforms in apoptosis

Abstract

The p53 protein is a major mediator of the cellular response to genotoxic stress and is a crucial suppressor of tumor formation. In a variety of organisms, p53 and its paralogs, p63 and p73, each encode multiple protein isoforms through alternative splicing, promoters, and translation start sites. The function of these isoforms in development and disease are still being defined. Here, we evaluate the apoptotic potential of multiple isoforms of the single p53 gene in the genetic model Drosophila melanogaster. Most previous studies have focused on the p53A isoform, but it has been recently shown that a larger p53B isoform can induce apoptosis when overexpressed. It has remained unclear, however, whether one or both isoforms are required for the apoptotic response to genotoxic stress. We show that p53B is a much more potent inducer of apoptosis than p53A when overexpressed. Overexpression of two newly identified short isoforms perturbed development and inhibited the apoptotic response to ionizing radiation. Analysis of physiological protein expression indicated that p53A is the most abundant isoform, and that both p53A and p53B can form a complex and co-localize to sub-nuclear compartments. In contrast to the overexpression results, new isoformspecific loss-of-function mutants indicated that it is the shorter p53A isoform, not full-length p53B, that is the primary mediator of pro-apoptotic gene transcription and apoptosis after ionizing radiation. Together, our data show that it is the shorter p53A isoform that mediates the apoptotic response to DNA damage, and further suggest that p53B and shorter isoforms have specialized functions.

VCP functions to maintain nuclear size by managing DNA damage-induced MDC1–p53–autophagy axis

“…Our study suggests the nuclear expansion defect, caused by TER94 dysfunction or Mu2overexpression, selectively requires p53A. Previous studies have suggested that p53A is required for DNA damage-induced apoptosis in dividing cells by activating proapoptotic genes40 , and this isoform also showed a tumor-suppressor function by inducing apoptosis and necrosis during spermatogenesis54 . A recent report suggests that Drosophila p53A and p53B have opposing effect on autophagy and apoptosis, and it is the balance between these p53 isoforms that mediate this cellular life-and-death decision under duress44 .…”

miR‐34a inhibits the apoptosis of MDSCs by suppressing the expression of N‐myc

“…Whether c‐myc or N‐myc is deleted, it will result in embryonic lethality through various defects in organs and tissues. As we all know, p53 gene is so far the most related gene to human tumors, which could arrest cell cycle and promote apoptosis, maintain the genome stability and inhibit tumor angiogenesis 37 , 38 , 39 , 40 . In all malignant tumors, there will be >50% mutations of p53 gene.…”

“…As we all know, p53 gene is so far the most related gene to human tumors, which could arrest cell cycle and promote apoptosis, maintain the genome stability and inhibit tumor angiogenesis. [37][38][39][40] In miR-34a inhibits MDSCs' apoptosis via N-myc S Chen et al all malignant tumors, there will be 450% mutations of p53 gene. Abnormal expression of Myc could induce apoptosis by ARF/p53 signaling pathway, showing the oncogenic phenotype.…”

Drosophila p53 integrates the antagonism between autophagy and apoptosis in response to stress

“…The p53 (p53B) isoform refers to the fulllength p53 protein that has an intact transactivation domain and is structurally analogous to the human full-length TP53/ p53 [9,16,17]. The third, most recent discovered isoform, p53E, is a 334-amino acid protein with a unique 10-amino acid transactivation domain which presumably acts as a dominant negative [18].…”