Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

Abstract

A large body of literature describes elaborate NF-κB signaling networks induced by inflammatory and immune signals. Decades of research has revealed that transcriptionally functional NF-κB dimers are activated by two major pathways, canonical and non-canonical. Both pathways involve the release of NF-κB dimers from inactive cytoplasmic complexes to cause their nuclear translocation to modulate gene expression programs and biological responses. NF-κB is also responsive to genotoxic agents; however, signal communication networks that are initiated in the nucleus following DNA damage induction are less defined. Evidence in the literature supports the presence of such signaling pathways induced by multiple distinct genotoxic agents, resulting in the activation of cytoplasmic IKK complex. An example is a pathway that involves the DNA damage-responsive kinase ataxia telangiectasia mutated (ATM) and a series of post-translational modifications of NF-κB essential modulator (NEMO) in the nucleus of a genotoxinexposed cell. Recent evidence also suggests that this nuclear-initiated NF-κB signaling pathway plays significant physiological and pathological roles, particularly in lymphocyte development and human cancer progression. This review will summarize these new developments, while identifying significant unanswered questions and providing new hypotheses that may be addressed in future studies.

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

“…One of this pathway might be directly linked to DNA damage caused by temozolomide via the activation of the ataxia-telangiectasia-mutated protein complex or other mechanisms. [41][42][43][44] The other pathway is activated by the endogenous glutamate acting at mGlu3 receptors and is mediated by PtdIns-3-K (see Figure 6e). Thus, glutamate, the major excitatory neurotransmitter in the CNS, is not only involved in the regulation of tumor invasion and cell proliferation but also acts as a critical regulator of the intracellular signaling pathways that mediate chemoresistance, thereby limiting the clinical efficacy of standard chemotherapy with DNA-alkylating agents.…”

Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1

“…From a wider perspective, our findings of the 53BP1-NUP153/importin-b pathway as an important aspect of the DDR network add to an emerging evidence of subcellular trafficking as an integral part of genome surveillance. Such evidence encompasses ATM-regulated nuclear export 29 and import, 30 as well as the import of essential genome caretakers, such as the FANCD2, RAD51 or BRCA1 repair proteins, [31][32][33] ribonucleotide reductases, 34 DNA damageregulated transcription factors, 35 the ATM-activator protein Aven 36 or p53 tumor suppressor. 37 Although our overall understanding of the role(s) for mammalian NUPs and NPCs in genome maintenance is still in its infancy, significant advances in this research area have already been made based on experiments with yeast models.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…In response to DNA damage, nuclear ATM phosphorylates p53, which stabilizes the multi-functional transcription factor to induce its target genes, thus favoring cell cycle arrest and senescence over apoptosis (Xu and Baltimore, 1996;Sperka et al, 2012). Concurrently, a small pool of activated ATM translocates from the nucleus into the cytoplasm where it initiates a novel 'nucleus-to-cytoplasm' signaling pathway that promotes the NF-κB-dependent induction of anti-apoptotic Bcl-xL through an as-yet-unresolved mechanism (Miyamoto, 2011).…”