Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity

Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J. E., Premsrirut, P., Luo, W., Chicas, A., Lee, C. S., Kogan, S. C., Lowe, S. W. (October 2011) Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev, 25 (20). pp. 2125-36. ISSN 1549-5477 (Electronic) 0890-9369 (Linking)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/21979375
DOI: 10.1101/gad.17276711

Abstract

Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo 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 senescent chromatin, we identified the nuclear factor-kappaB (NF-kappaB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-kappaB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-kappaB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-kappaB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-kappaB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-kappaB that contributes to the outcome of cancer therapy.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Gene Targeting Service
CSHL Cancer Center Shared Resources > Microarray Service
CSHL labs > Lowe lab
Watson School > Publications
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User: CSHL Librarian
Date: 6 October 2011
Date Deposited: 07 Nov 2011 22:27
Last Modified: 30 Oct 2015 16:13
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15619

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