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

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

doi:10.18632/aging.100099

Cited by 66 publications

(68 citation statements)

References 53 publications

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“…The p53B isoform may also participate in other processes that Drosophila p53 has been implicated in, which include the culling of primordial germ cells, meiotic checkpoints, DNA repair, stem cell divisions, and tissue regeneration. 41,[60][61][62][63][64][65][66][67][68][69] Our results indicate that p53A and p53B localize to nuclear bodies and physically associate, an interaction that is likely direct through the conserved p53 oligomerization domain. Therefore, p53 tetramers may be heterogeneous and have different ratios of p53A and p53B subunits.…”

Section: Discussionmentioning

confidence: 64%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 64%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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“…P53 has been linked with aging in mammalian system. Like its mammalian counterpart, Drosophila P53 (dP53) plays a pivotal role in mediating DNA damage‐induced apoptosis and has been found to be involved in regulating aging (Waskar et al ., 2009). Our testing indicated that there was an increase in dP53 expression in older animals.…”

Section: Resultsmentioning

confidence: 99%

Anti‐inflammaging effects of human alpha‐1 antitrypsin

et al. 2017

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SummaryInflammaging plays an important role in most age‐related diseases. However, the mechanism of inflammaging is largely unknown, and therapeutic control of inflammaging is challenging. Human alpha‐1 antitrypsin (hAAT) has immune‐regulatory, anti‐inflammatory, and cytoprotective properties as demonstrated in several disease models including type 1 diabetes, arthritis, lupus, osteoporosis, and stroke. To test the potential anti‐inflammaging effect of hAAT, we generated transgenic Drosophila lines expressing hAAT. Surprisingly, the lifespan of hAAT‐expressing lines was significantly longer than that of genetically matched controls. To understand the mechanism underlying the anti‐aging effect of hAAT, we monitored the expression of aging‐associated genes and found that aging‐induced expressions of Relish (NF‐ĸB orthologue) and Diptericin were significantly lower in hAAT lines than in control lines. RNA‐seq analysis revealed that innate immunity genes regulated by NF‐kB were significantly and specifically inhibited in hAAT transgenic Drosophila lines. To confirm this anti‐inflammaging effect in human cells, we treated X‐ray‐induced senescence cells with hAAT and showed that hAAT treatment significantly decreased the expression and maturation of IL‐6 and IL‐8, two major factors of senescence‐associated secretory phenotype. Consistent with results from Drosophila, RNA‐seq analysis also showed that hAAT treatment significantly inhibited inflammation related genes and pathways. Together, our results demonstrated that hAAT significantly inhibited inflammaging in both Drosophila and human cell models. As hAAT is a FDA‐approved drug with a confirmed safety profile, this novel therapeutic potential may make hAAT a promising candidate to combat aging and aging‐related diseases.

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“…This was most clearly demonstrated by the study by Waskar et al 20 showing that p53 influences life span in flies in p53 dose-specific, fly tissue-specific, developmental stage-specific, and sexspecific manners. Furthermore, the type and extent of stress that activates p53 could also be a factor to determine Figure 3.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 90%

“…Furthermore, although overexpression of wild-type p53 at a high level in the larval stage was toxic to larval development, overexpression of p53 at a moderate level extended life span in both males and females. 20 Thus, the regulation of life span by p53 in flies is context dependent; it appears to be not only p53 dose specific but also fly tissue, sex, and developmental stage specific. …”

Section: P53 and Longevity In Drosophilamentioning

confidence: 99%

“…Interestingly, it has been found that caloric restriction, Sir2 overexpression, or treatment with resveratrol could not further extend the life span in DN Dmp53-overexpressing flies, suggesting that DN Dmp53, caloric restriction, and Sir2 act through similar pathways of longevity extension. 19 Taking advantage of the Drosophila Gene-Switch system that puts transcriptional control of a transgene under temporal control, Waskar et al 20 extensively investigated the impact of p53 on life span by conditional overexpression of both wild-type and DN dmp53 in flies. They first confirmed earlier studies by Helfand's laboratory, 18,19 which demonstrated that the expression of DN dmp53 in neuronal cells extended life span in flies.…”

Section: P53 and Longevity In Drosophilamentioning

confidence: 99%

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The Regulation of Aging and Longevity: A New and Complex Role of p53

Feng

Lin

2011

Genes & Cancer

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Abstractp53 plays a critical role in tumor suppression. As a transcription factor, in response to stress signals, p53 regulates its target genes and initiates stress responses, including cell cycle arrest, apoptosis, and/or senescence, to exert its function in tumor suppression. Emerging evidence has suggested that p53 is also an important but complex player in the regulation of aging and longevity in worms, flies, mice, and humans. Whereas p53 accelerates the aging process and shortens life span in some contexts, p53 can also extend life span in some other contexts. Thus, p53 appears to regulate aging and longevity in a context-dependent manner. Here, the authors review some recent advances in the study of the role of p53 in the regulation of aging and longevity in both invertebrate and vertebrate models. Furthermore, they discuss the potential mechanisms by which p53 regulates aging and longevity, including the p53 regulation of insulin/TOR signaling, stem/progenitor cells, and reactive oxygen species.

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

Cited by 66 publications

References 53 publications

The function of Drosophila p53 isoforms in apoptosis

The function of Drosophila p53 isoforms in apoptosis

Anti‐inflammaging effects of human alpha‐1 antitrypsin

The Regulation of Aging and Longevity: A New and Complex Role of p53

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