Article

NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-α feedforward signaling.

Department of Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Cell (Impact Factor: 33.12). 04/2011; 145(1):92-103. DOI: 10.1016/j.cell.2011.02.023
Source: PubMed

ABSTRACT Upon DNA damage, ataxia telangiectasia mutated (ATM) kinase triggers multiple events to promote cell survival and facilitate repair. If damage is excessive, ATM stimulates cytokine secretion to alert neighboring cells and apoptosis to eliminate the afflicted cell. ATM augments cell survival by activating nuclear factor (NF)-κB; however, how ATM induces cytokine production and apoptosis remains elusive. Here we uncover a p53-independent mechanism that transmits ATM-driven cytokine and caspase signals upon strong genotoxic damage. Extensive DNA lesions stimulated two sequential NF-κB activation phases, requiring ATM and NEMO/IKK-γ: The first phase induced TNF-α-TNFR1 feedforward signaling, promoting the second phase and driving RIP1 phosphorylation. In turn, RIP1 kinase triggered JNK3/MAPK10-dependent interleukin-8 secretion and FADD-mediated proapoptotic caspase-8 activation. Thus, in the context of excessive DNA damage, ATM employs NEMO and RIP1 kinase through autocrine TNF-α signaling to switch on cytokine production and caspase activation. These results shed light on cell-fate regulation by ATM.

1 Follower
 · 
197 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Exposure to ionizing radiation modulates immune responses in a complex dose-dependent pattern, with possible anti-inflammatory effects in the low dose range, expression of pro-inflammatory cytokines at moderate doses and immunosuppression after exposure to higher doses due to precursor cell death together with concomitant exacerbated innate immune responses. A central regulator in the immune system is the transcription factor Nuclear Factor κB (NF-κB). NF-κB is involved in the regulation of cellular survival, immune responses and inflammation, resulting in eminent importance in cancerogenesis. After exposure to ionizing radiation, NF-κB activation is initially triggered by ATM which is activated by DNA double strand breaks. Together with the NF-κB essential modulator (NEMO), it serves as a nucleoplasmic shuttle. The pathway converges with the classical NF-κB pathway at IκB kinase (IKK) complex activation. Resulting cytokine expression can activate NF-κB in a positive feed forward loop. Danger signals released from dying cells can activate NF-κB via Toll-like receptors (TLRs). The resulting immune activation can be beneficial or detrimental. In the low dose range, pro- and anticancerogenic effects are possible. In the radiotherapy-relevant dose range, tolerogenic immune responses should be avoided, and an anti-tumor immune response might be supported by TLR agonists activating NF-κB. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 02/2015; DOI:10.1016/j.canlet.2015.02.019 · 5.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Regulated cell death has essential functions in development and in adult tissue homeostasis. Necroptosis is a newly discovered pathway of regulated necrosis that requires the proteins RIPK3 and MLKL and is induced by death receptors, interferons, toll-like receptors, intracellular RNA and DNA sensors, and probably other mediators. RIPK1 has important kinase-dependent and scaffolding functions that inhibit or trigger necroptosis and apoptosis. Mouse-model studies have revealed important functions for necroptosis in inflammation and suggested that it could be implicated in the pathogenesis of many human inflammatory diseases. We discuss the mechanisms regulating necroptosis and its potential role in inflammation and disease.
    Nature 01/2015; 517(7534):311-20. DOI:10.1038/nature14191 · 42.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Targeted cancer therapy using small molecule inhibitors (SMIs) has been useful in targeting the tumor cells while sparing the normal cells. Despite clinical success of many targeted therapies, their off-target effects and development of resistance are emerging as significant and challenging problems. Thus, there is an urgent need to identify targets to devise new means to treat cancers and their drug-resistant phenotypes. CARP-1/CCAR1 (Cell division cycle and apoptosis regulator 1), a peri-nuclear phospho-protein, plays a dynamic role in regulating cell growth and apoptosis by serving as a co-activator of steroid/thyroid nuclear receptors, β-catenin, Anaphase Promoting Complex/Cyclosome (APC/C) E3 ligase, and tumor suppressor p53. CARP-1/CCAR1 also regulates chemotherapy-dependent apoptosis. CARP-1/CCAR1 functional mimetics (CFMs) are a novel SMIs of CARP-1/CCAR1 interaction with APC/C. CFMs promote apoptosis in a manner independent of p53. CFMs are potent inhibitors of a variety of cancer cells including the drug (Adriamycin or Tamoxifen)-resistant breast cancer cells but not the immortalized breast epithelial cells, while a nano-lipid formulation of the lead compound CFM-4 improves its bioavailability and efficacy in vivo when administered orally. This review focuses on the background and pleiotropic roles of CARP-1/CCAR1 as well as its apoptosis signaling mechanisms in response to chemotherapy in cancer cells.
    Oncotarget 03/2015; 6(9):6499-6510. · 6.63 Impact Factor

Preview

Download
116 Downloads
Available from