Drosophila melanogaster p53 has developmental stage-specific and sex-specific effects on adult life span indicative of sexual antagonistic pleiotropy

Morris Waskar,Jie Shen,Kevin Tozer,John Tower,Dmitriy Skvortsov,Diana Abdueva,Gary N Landis,Simon Tavaré,Christina Curtis

doi:10.18632/aging.100099

Abstract

Truncated and mutant forms ofp53 affect life span in Drosophila, nematodes and mice, however the role of wild-type p53 in aging remains unclear. Here conditional over-expression of both wild-type and mutant p53 transgenes indicated that, in adult flies, p53 limits life span in females but favors life span in males. In contrast, during larval development, moderate over-expression of p53 produced both male and female adults with increased life span. Mutations of the endogenous p53 gene also had sex-specific effects on life span under control and stress conditions: null mutation of p53 increased life span in females, and had smaller, more variable effects in males. These developmental stage-specific and sex-specific effects of p53 on adult life span are consistent with a sexual antagonistic pleiotropy model.

Highlights

The p53 gene encodes a transcription factor that regulates apoptosis and metabolism and is mutated in the majority of human cancers [1, 2]
All of the flies examined in this study are the progeny of a cross; for example “16-9” flies are the progeny of a cross of males of strain 16 with females of strain 9 to generate progeny containing both constructs; in all cases crosses are indicated with the male parent genotype first, and the female parent genotype second
Because these Drosophila p53 dominant mutation transgenes are generally expected to antagonize the activity of wild-type p53, the data are consistent with wild-type p53 having a negative effect on adult female life span

Summary

Introduction

The p53 gene encodes a transcription factor that regulates apoptosis and metabolism and is mutated in the majority of human cancers [1, 2]. The p53 protein functions as a tetramer with various protein domains mediating oligomerization, DNA binding and transcriptional transactivation. The other domains of Dmp show less obvious sequence similarity to Hp53, but appear conserved in function. Similar to the Nterminal transcriptional activation domain of Hp53, the N-terminus of Dmp contains a high proportion of acidic residues, and Dmp has been shown to bind to conserved p53 response elements and activate transcription [3]. The C-terminus of Hp53 contains a basic region (9/26 residues) that can bind either DNA or RNA, and the C-terminus of Dmp is relatively basic (6/24 residues). The oligomerization domain is located in the C-terminal portion of Hp53, and the corresponding region of Dmp contains a conserved critical Gly “hinge” residue, and appears active in oligimerization based on yeast two hybrid assays. The p53 message is expressed at very low levels in adult tissues, with some enrichment indicated for the eye, malphigian tubule (similar to mammalian kidney), and female germ cells [7, 8]

Methods

Results

Conclusion