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Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.
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Immanuel kant
May 23, 2012, 12:20:50 AM5/23/12
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Genes Dev.2011 Oct 15;25(20):2125-36. doi: 10.1101/gad.17276711. Epub
2011 Oct 6.
Control of the senescence-associated secretory phenotype by NF-κB
promotes senescence and enhances chemosensitivity.
Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut
P, Luo W, Chicas A, Lee CS, Kogan SC, Lowe SW.
SourceCold Spring Harbor Laboratory, New York 11724, USA.
Abstract
Cellular senescence acts as a potent barrier to tumorigenesis and
contributes to the anti-tumor activity of certain chemotherapeutic
agents. Senescent cellsundergo a stable cell cycle arrest controlled
by RB and p53 and, in addition, display a senescence-associated
secretory phenotype (SASP) involving the production of factors that
reinforce the senescence arrest, alter the microenvironment, and
trigger immune surveillance of the senescent cells. Through a
proteomics analysis of senescentchromatin, we identified the nuclear
factor-κB (NF-κB) subunit p65 as a major transcription factor that
accumulates on chromatin of senescent cells. We found that NF-κB acts
as a master regulator of the SASP, influencing the expression of more
genes than RB and p53 combined. In cultured fibroblasts, NF-κB
suppression causes escape from immune recognition by natural killer
(NK) cellsand cooperates with p53 inactivation to bypass senescence.
In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced
senescence, producing drug resistance, early relapse, and reduced
survival. Our results demonstrate that NF-κB controls both cell-
autonomous and non-cell-autonomous aspects of the senescence program
and identify a tumor-suppressive function of NF-κB that contributes to
the outcome of cancer therapy.
Comment in
Nat Rev Cancer. 2011 Dec;11(12):832-3.
PMID: 21979375 [PubMed
2011 Oct 6.
Control of the senescence-associated secretory phenotype by NF-κB
promotes senescence and enhances chemosensitivity.
Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut
P, Luo W, Chicas A, Lee CS, Kogan SC, Lowe SW.
SourceCold Spring Harbor Laboratory, New York 11724, USA.
Abstract
Cellular senescence acts as a potent barrier to tumorigenesis and
contributes to the anti-tumor activity of certain chemotherapeutic
agents. Senescent cellsundergo a stable cell cycle arrest controlled
by RB and p53 and, in addition, display a senescence-associated
secretory phenotype (SASP) involving the production of factors that
reinforce the senescence arrest, alter the microenvironment, and
trigger immune surveillance of the senescent cells. Through a
proteomics analysis of senescentchromatin, we identified the nuclear
factor-κB (NF-κB) subunit p65 as a major transcription factor that
accumulates on chromatin of senescent cells. We found that NF-κB acts
as a master regulator of the SASP, influencing the expression of more
genes than RB and p53 combined. In cultured fibroblasts, NF-κB
suppression causes escape from immune recognition by natural killer
(NK) cellsand cooperates with p53 inactivation to bypass senescence.
In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced
senescence, producing drug resistance, early relapse, and reduced
survival. Our results demonstrate that NF-κB controls both cell-
autonomous and non-cell-autonomous aspects of the senescence program
and identify a tumor-suppressive function of NF-κB that contributes to
the outcome of cancer therapy.
Comment in
Nat Rev Cancer. 2011 Dec;11(12):832-3.
PMID: 21979375 [PubMed
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