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-kB (NF-kB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-kB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-kB 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-kB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-kB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-kB that contributes to the outcome of cancer therapy.

The monomeric RalGTPases, RalA and RalB are recognized as components of a regulatory framework supporting tumorigenic transformation. Specifically, RalB is required to suppress apoptotic checkpoint activation, the mechanistic basis of which is unknown. Reported effector proteins of RalB include the Sec5 component of the exocyst, an octameric protein complex implicated in tethering of vesicles to membranes. Surprisingly, we find that the RalB/Sec5 effector complex directly recruits and activates the atypical IkappaB kinase family member TBK1. In cancer cells, constitutive engagement of this pathway, via chronic RalB activation, restricts initiation of apoptotic programs typically engaged in the context of oncogenic stress. Although dispensable for survival in a nontumorigenic context, this pathway helps mount an innate immune response to virus exposure. These observations define the mechanistic contribution of RalGTPases to cancer cell survival and reveal the RalB/Sec5 effector complex as a component of TBK1-dependent innate immune signaling.

The monomeric RAL (RAS-like) GTPases have been indirectly implicated in mitogenic regulation and cell transformation. Here, we show that RALA and RALB collaborate to maintain tumorigenicity through regulation of both proliferation and survival. Remarkably, this task is divided between these highly homologous isoforms. RALB is specifically required for survival of tumour cells but not normal cells. RALA is dispensable for survival, but is required for anchorage-independent proliferation. Reducing the 'oncogenic burden' in human tumour cells relieves the sensitivity to loss of RALB. These observations establish RAL GTPases as crucial components of the cellular machinery that are exploited by factors that drive oncogenic transformation.

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Cellular senescence limits the proliferative capacity of damaged cells and thereby acts as an intrinsic mechanism of tumor suppression. In this issue, Wajapeyee et al. (2008) identify insulin growth factor binding protein 7 (IGFBP7) as a secreted factor that mediates senescence induced by oncogenic BRAF in normal melanocytes. In addition, IGFBP7 triggers apoptosis in cells that have progressed to melanoma, suggesting a new approach for melanoma treatment.