SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes

Aging
Emmanuelle Saint-GermainGerardo Ferbeyre

Abstract

The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition. We identified a set of SOCS1-dependent p53 target genes that include several secreted proteins and genes regulating oxidative metabolism and ferroptosis. Exogenous SOCS1 was sufficient to regulate the expression of p53 target genes and sensitized cells to ferroptosis. This effect correlated with the ability of SOCS1 to reduce the expression of the cystine transporter SLC7A11 and the levels of glutathione. SOCS1 and SOCS1-dependent p53 target genes were induced during the senescence response to oncogenic STAT5A, RasV12 or the tumor suppressor PML. However, while SOCS1 sensitized cells to ferroptosis neither RasV12 nor STAT5A mimicked the effect. Intriguingly, PML turned cells highly resistant to ferroptosis. The results indicate different susceptibilities to ferroptosis in senescent cells depending on the trigger and suggest the p...Continue Reading

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Citations

Jun 30, 2019·Pharmaceuticals·Shashank MasaldanAshley I Bush
Dec 12, 2018·Aging·Piervito LoprioreIvano Amelio
Nov 20, 2018·Frontiers in Oncology·Weifen ZhangWentong Li
Mar 31, 2019·Journal of Hematology & Oncology·Yanhua MouBin Li
May 7, 2020·Frontiers in Neuroscience·Xiaohua Song, Dingxin Long
Sep 29, 2019·Cancers·Sebastian IgelmannGerardo Ferbeyre
May 19, 2019·Cancer Research·Emmanuelle Saint-GermainGerardo Ferbeyre
Jan 12, 2021·Oxidative Medicine and Cellular Longevity·Jinghan ZhuWanguang Zhang
Jan 30, 2021·Frontiers in Cell and Developmental Biology·Zhen WeiPing Yi
Jan 29, 2021·Investigational New Drugs·Man-Ru LiuDong-Sheng Pei
Apr 24, 2021·Journal of Pharmaceutical and Biomedical Analysis·Jing YuHonghao Zhou
Sep 4, 2021·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Antero SalminenAnu Kauppinen
Nov 16, 2021·Naunyn-Schmiedeberg's Archives of Pharmacology·Yifan ZhangLiangming Zhu
Dec 7, 2021·Frontiers in Cell and Developmental Biology·Mei ChenShufang Zhang
Nov 26, 2021·Expert Opinion on Therapeutic Targets·Long YeYun Dai

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Datasets Mentioned

BETA
GSE98216

Methods Mentioned

BETA
immunoprecipitation
PML
Co-Immunoprecipitation
pull down
co-IP
RNA collection
electrophoresis
Assay
PCR
Chip

Software Mentioned

Transcriptome Analysis Console
DAVID
Gene set enrichment analysis ( GSEA
DiRE
GraphPad Prism
Affymetrix Expression Console

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