4790

NFKB1

nuclear factor of kappa light polypeptide gene enhancer in B-cells 1;NFKB1;nuclear factor of kappa light polypeptide gene enhancer in B-cells 1

DNA binding factor KBF1|DNA-binding factor KBF1|NF-kappabeta|nuclear factor NF-kappa-B p105 subunit|nuclear factor NF-kappa-B p50 subunit|nuclear factor kappa-B DNA binding subunit

4q24

protein-coding

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.