DNA damage‐dependent NF‐κB activation: NEMO turns nuclear signaling inside out

Abstract

Summary The dimeric transcription factor nuclear factor κB (NF-κB) functions broadly in coordinating cellular responses during inflammation and immune reactions, and its importance in the pathogenesis of cancer is increasingly recognized. Many of the signal transduction pathways that trigger activation of cytoplasmic NF-κB in response to a broad array of immune and inflammatory stimuli have been elaborated in great detail. NF-κB can also be activated by DNA damage, though relatively less is known about the signal transduction mechanisms that link DNA damage in the nucleus with activation of NF-κB in the cytoplasm. Here, we focus on the conserved signaling pathway that has emerged that promotes NF-κB activation following DNA damage. Post-translational modification of NF-κB essential modulator (NEMO) plays a central role in linking the cellular DNA damage response to NF-κB via the ataxia telangiectasia mutated (ATM) kinase. Accumulating evidence suggests that DNA damage-dependent NF-κB activation may play significant biological roles, particularly during lymphocyte differentiation and progression of human malignancies.

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

“…Current models suggest that DNA damage increases nuclear export of ATM into the cytoplasm. 44,45 However, our determination that PACS-2 is required for redistribution of ATM to the cytoplasm and that cytoplasmic PACS-2 interacts with ATM suggests that Figure 6 Cytoplasmic PACS-2 mediates Bcl-xL reporter expression. HCT116 cells were transfected with a luciferase expression plasmid under the control of p21 or Bcl-xL promoter together with PACS-2 or PACS-2ΔNLS and the transcription factor p53 or p65.…”

Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors

“…A final possibility is that BET proteins may mediate "inside-out" signaling from the nucleus to the cytoplasm that modulates IKK activity. Precedent for this type of signaling comes from analysis of DNA damage-induced activation of IKK, which relies on ATM-dependent phosphorylation of nuclear IKKγ (NEMO) (27). However, an inhibitor of ATM kinase that blocks DNA damage-induced IKK activation had no effect on IKK activity or the viability of ABC DLBCL cells, demonstrating that any potential inside-out signaling in these cells is mechanistically distinct (Fig.…”

Paulownia tomentosa (Princess Tree) Extract Reduces DNA Damage and Induces DNA Repair Processes in Skin Cells

“…These diseases are characterized at the level of the skin by extreme sensitivity to sunlight, resulting in sunburn, pigmentation changes, an early onset of the appearance of skin aging signs and a greatly elevated incidence of skin cancers in particular for XP disorder [12]. These changes can be explained by long lasting DNA damages that induces prolonged cellular inflammation through the activation of the NF-κB pathway [2,13,14,15,16] and an acquired immune deficiency [17] as well as rapid accumulation of mutation leading to cell apoptosis, senescence and cell tumorigenesis [18,19,20,21].…”

“…In response to DSB, PIDD as well as ATM are capable of initiating cascades leading to pro-or antiapoptotic signals, NF-κB presumably being a part of the pro-survival cascade [61]. Miyamoto et al, have summarized this model of NF-κB activation by DNA damage as a 'two signal' model as it requires coincident NEMO SUMOylation and ATM activation by double strand breaks to permit robust NF-κB activation [15]. Taken together these findings suggest that NF-κB may be both have both causal and effector roles in the development of DNA damage [2].…”

“…Nuclear DNA double strand breaks (DSBs) are one of the most potent DNA damage signals to activate NF-κB [2]. This process can occur within 1-2 h after break induction through activation of the canonical inhibitor of κB (IκB) kinase (IKK) complex and IκBa degradation [15]. NF-κB can be activated by Topoisomerase inhibitors (such as camptothecin) potentially via the generation of double strand breaks as well [16].…”