Fine-tuning of PI3K/AKT signalling by the tumour suppressor PTEN is required for maintenance of flight muscle function and mitochondrial integrity in ageing adult drosophila melanogaster

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题名:	Fine-tuning of PI3K/AKT signalling by the tumour suppressor PTEN is required for maintenance of flight muscle function and mitochondrial integrity in ageing adult drosophila melanogaster
作者:	范世榮;Mensah, Lawrence B.;Davison, Claire;Fan, Shih-Jung;Morris, John F.;Goberdhan, Deborah C. I.;Wilson, Clive
贡献者:	生醫理工學院生命科學系
关键词:	1-Phosphatidylinositol 3-kinase;Aberration;Adults;Age;Aging;AKT protein;Alleles;Anatomy & physiology;Animals;Apoptosis;Autophagy;Bcl-2 protein;Cancer;Cell cycle;Cell death;Cell growth;Cellular stress response;Chromosome 10;Defects;Diabetes mellitus;Disease;Drosophila;Drosophila melanogaster;Drosophila Proteins - genetics;Drosophila Proteins - metabolism;Energy balance;Female;Flight;Flight muscle;Fruit flies (Tephritidae);Genetics;Genotype & phenotype;Homeostasis;Homology;In vivo methods and tests;Insects;Insulin;Integrity;Kinases;Lipids;Metabolism;Mitochondria;Muscle function;Muscles;Mutation;Neurodegeneration;Neurodegenerative diseases;Oxidative stress;Phosphatase;Phosphatases;Phosphatidylinositol 3-Kinases - genetics;Phosphatidylinositol 3-Kinases - metabolism;Physiology;Protein Binding;Proteins;Proto-Oncogene Proteins c-akt - genetics;Proto-Oncogene Proteins c-akt - metabolism;PTEN Phosphohydrolase - genetics;PTEN Phosphohydrolase - metabolism;PTEN protein;Rapamycin;Rodents;Signal Transduction;Signaling;Tensin;TOR protein;Tumors
日期:	2015-11-01
上传时间:	2026-04-23 11:12:44 (UTC+8)
出版者:	Public Library of Science;United States: Public Library of Science
摘要:	摘要： Insulin/insulin-like growth factor signalling (IIS), acting primarily through the PI3-kinase (PI3K)/AKT kinase signalling cassette, plays key evolutionarily conserved regulatory roles in nutrient homeostasis, growth, ageing and longevity. The dysfunction of this pathway has been linked to several age-related human diseases including cancer, Type 2 diabetes and neurodegenerative disorders. However, it remains unclear whether minor defects in IIS can independently induce the age-dependent functional decline in cells that accompany some of these diseases or whether IIS alters the sensitivity to other aberrant signalling. We identified a novel hypomorphic allele of PI3K's direct antagonist, Phosphatase and tensin homologue on chromosome 10 (Pten), in the fruit fly, Drosophila melanogaster. Adults carrying combinations of this allele, Pten5, combined with strong loss-of-function Pten mutations exhibit subtle or no increase in mass, but are highly susceptible to a wide range of stresses. They also exhibit dramatic upregulation of the oxidative stress response gene, GstD1, and a progressive loss of motor function that ultimately leads to defects in climbing and flight ability. The latter phenotype is associated with mitochondrial disruption in indirect flight muscles, although overall muscle structure appears to be maintained. We show that the phenotype is partially rescued by muscle-specific expression of the Bcl-2 homologue Buffy, which in flies, maintains mitochondrial integrity, modulates energy homeostasis and suppresses cell death. The flightless phenotype is also suppressed by mutations in downstream IIS signalling components, including those in the mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway, suggesting that elevated IIS is responsible for functional decline in flight muscle. Our data demonstrate that IIS levels must be precisely regulated by Pten in adults to maintain the function of the highly metabolically active indirect flight muscles, offering a new system to study the in vivo roles of IIS in the maintenance of mitochondrial integrity and adult ageing. 其他題名： PLoS One 出版者： United States: Public Library of Science 出版日期： 2015-11-23 出處： PloS one, 2015-11, Vol.10 (11), p.e0143818-e0143818 資源來源： Agricultural & Environmental Science Collection 版權： COPYRIGHT 2015 Public Library of Science 版權： 2015 Mensah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 版權： 2015 Mensah et al 2015 Mensah et al 識別號： ISSN: 1932-6203 識別號： EISSN: 1932-6203 識別號： DOI: 10.1371/journal.pone.0143818 識別號： PMID: 26599788
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