The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4

Chanhee Kang; Qikai Xu; Timothy D Martin; Mamie Z Li; Marco Demaria; Liviu Aron; Tao Lu; Bruce A Yankner; Judith Campisi; Stephen J Elledge

doi:10.1126/science.aaa5612

The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4

Chanhee Kang
, Qikai Xu
, Timothy D Martin
, Mamie Z Li
, Marco Demaria
, Liviu Aron
, Tao Lu
, Bruce A Yankner
, Judith Campisi
, Stephen J Elledge

Research output: Contribution to journal › Article › Academic › peer-review

816 Citations (Scopus)

Abstract

Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.

Original language	English
Pages (from-to)	aaa5612
Journal	Science
Volume	349
Issue number	6255
DOIs	https://doi.org/10.1126/science.aaa5612
Publication status	Published - 25-Sept-2015
Externally published	Yes

Keywords

Aging
Animals
Ataxia Telangiectasia Mutated Proteins
Autophagy
Brain
Cell Aging
Cell Cycle
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16
DNA Damage
Fibroblasts
GATA4 Transcription Factor
Gene Expression Profiling
Humans
Inflammation
Interleukin-1alpha
Mice
Mice, Inbred C57BL
MicroRNAs
NF-kappa B
Phenotype
Promoter Regions, Genetic
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Tumor Suppressor Protein p53

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@article{d3cda2fc6a1145ca931f482d4ed4371d,

title = "The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4",

abstract = "Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.",

keywords = "Aging, Animals, Ataxia Telangiectasia Mutated Proteins, Autophagy, Brain, Cell Aging, Cell Cycle, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, DNA Damage, Fibroblasts, GATA4 Transcription Factor, Gene Expression Profiling, Humans, Inflammation, Interleukin-1alpha, Mice, Mice, Inbred C57BL, MicroRNAs, NF-kappa B, Phenotype, Promoter Regions, Genetic, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Tumor Suppressor Protein p53",

author = "Chanhee Kang and Qikai Xu and Martin, \{Timothy D\} and Li, \{Mamie Z\} and Marco Demaria and Liviu Aron and Tao Lu and Yankner, \{Bruce A\} and Judith Campisi and Elledge, \{Stephen J\}",

note = "Copyright {\textcopyright} 2015, American Association for the Advancement of Science.",

year = "2015",

month = sep,

day = "25",

doi = "10.1126/science.aaa5612",

language = "English",

volume = "349",

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T1 - The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4

AU - Kang, Chanhee

AU - Xu, Qikai

AU - Martin, Timothy D

AU - Li, Mamie Z

AU - Demaria, Marco

AU - Aron, Liviu

AU - Lu, Tao

AU - Yankner, Bruce A

AU - Campisi, Judith

AU - Elledge, Stephen J

PY - 2015/9/25

Y1 - 2015/9/25

N2 - Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.

AB - Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.

KW - Aging

KW - Animals

KW - Ataxia Telangiectasia Mutated Proteins

KW - Autophagy

KW - Brain

KW - Cell Aging

KW - Cell Cycle

KW - Cells, Cultured

KW - Cyclin-Dependent Kinase Inhibitor p16

KW - DNA Damage

KW - Fibroblasts

KW - GATA4 Transcription Factor

KW - Gene Expression Profiling

KW - Humans

KW - Inflammation

KW - Interleukin-1alpha

KW - Mice

KW - Mice, Inbred C57BL

KW - MicroRNAs

KW - NF-kappa B

KW - Phenotype

KW - Promoter Regions, Genetic

KW - Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

KW - Tumor Suppressor Protein p53

U2 - 10.1126/science.aaa5612

DO - 10.1126/science.aaa5612

M3 - Article

C2 - 26404840

SN - 0036-8075

VL - 349

SP - aaa5612

JO - Science

JF - Science

IS - 6255

ER -

The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4

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Keywords

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