RRC ID 67071
Author Kano Y, Hiragami F, Motoda H, Akiyama J, Koike Y, Gomita Y, Inoue S, Kawaura A, Furuta T, Kawamura K.
Title C-SH2 point mutation converts p85β regulatory subunit of phosphoinositide 3-kinase to an anti-aging gene.
Journal Sci Rep
Abstract Insulin interacts with the insulin receptor, and the activated receptor promotes activity of the phosphoinositide-3 kinase (PI3K) enzyme. A decrease in insulin or insulin-like growth factor 1 (IGF-1) signaling increases the lifespan in mammalian species. We found that a point mutation in the C-SH2 domain of the p85β regulatory subunit of PI3K results in a prolonged lifespan. In p85β mutant cells, nerve growth factor (NGF) activates the longevity protein FOXO, and the mutant p85β gene produces strong resistance to oxidative stress, which contributes to aging. The p85β gene mutation causes increased serum insulin and low blood glucose in p85β mutant transgenic mice. Our results indicate that the p85β mutant allele alters the activity of downstream targets of PI3K by NGF and platelet-derived growth factor (PDGF) but not by insulin. We report that a point mutation in the C-SH2 domain of p85β transforms p85β into a novel anti-aging gene by abnormally regulating PI3K.
Volume 9(1)
Pages 12683
Published 2019-9-3
DOI 10.1038/s41598-019-48157-6
PII 10.1038/s41598-019-48157-6
PMID 31481652
PMC PMC6722097
MeSH Aging* Animals Blood Glucose / analysis Class I Phosphatidylinositol 3-Kinases / genetics Class I Phosphatidylinositol 3-Kinases / metabolism* Class Ia Phosphatidylinositol 3-Kinase / genetics Class Ia Phosphatidylinositol 3-Kinase / metabolism Female Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism Insulin / blood Male Mice Mice, Inbred C57BL Mice, Transgenic Nerve Growth Factor / pharmacology Oxidative Stress / drug effects PC12 Cells Platelet-Derived Growth Factor / pharmacology Point Mutation Proto-Oncogene Proteins c-akt / metabolism Rats src Homology Domains / genetics
IF 3.998
DNA material pcDNA3.1(-)-p85 beta mutant (RDB18722) pcDNA3.1(-)-FLAG-p85 beta mutant (RDB18723)