期刊
GENES & DEVELOPMENT
卷 25, 期 20, 页码 2125-2136出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.17276711
关键词
NF-kappa B; SASP; senescence; lymphoma; chemoresistance
资金
- Ellison Medical Foundation/American Federation for Aging Research
- Lauri Strauss Leukemia Foundation
- Angel Foundation
- National Health and Medical Research Council of Australia
- National Natural Science Foundation of China [60905013, 91019016, 31061160497]
- Leukemia and Lymphoma Society [SCOR 7015-09]
- NIH [CA122715, RR021239, CA143177, AG16379]
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-kappa B (NF-kappa B) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-kappa B acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-kappa B 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-kappa B inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-kappa B controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-kappa B that contributes to the outcome of cancer therapy.
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