IκB Kinase-Independent IκBα Degradation Pathway: Functional NF-κB Activity and Implications for Cancer Therapy

摘要: The transcription factor NF-κB has been documented to play roles in innate and adaptive immune responses (19). Deregulated activity of pathway also observed linked the progression several human malignancies (27). It is becoming increasingly clear that can modulate multiple aspects cell growth death (10). Understanding regulation likely shed insight into cancer treatment. NF-κB, a dimer two similar or heterologous subunits, predominantly found cytoplasm complexed with IκB family inhibitory molecules (37). Degradation proteins response stimuli an obligatory step activation (14). This degradation mediated by proteasome requires are phosphorylated at specific serine residues (4). Hence, role kinases (IKKs), IKK1 (also called IKKα) IKK2 IKKβ), which induce signal-dependent phosphorylation molecules, extensively investigated. cytoplasmic >700-kDa complex containing receives transmits various lead IκBα DNA binding. Apart from IKK enzymes, believed consist other known unknown might have regulatory chaperone-like functions (5, 39). Mice were homozygous null for both die embryonic day 9.5 (18). Mouse embryo fibroblasts (MEFs) derived IKK1/2−/− double knockout embryos severely defective activation, “classical” such as cytokines bacterial products recognized pattern recognition receptors These results emphasize absolutely essential (18). The rate-limiting be its release inhibitor retain additionally inhibit DNA-binding ability. Defective mechanistically persistent nuclear seen many tumors However, genetic modifications subsequent now thought necessary generating functional context target genes. changes, mainly initiated selective phosphorylation, increase interaction p300/CBP chromatin remodeling factors. Several kinases, including GSK3, NIK, CKII, PKA, PKCζ, TBK/t2k/NAK, themselves required modifying after Since same catalytic modification, it difficult dissect contribution IKKs processes IκB. In present study, using MEFs, we decipher novel mechanism anticancer agent doxorubicin (DoxR), independent IKK2. Further, treatment MEFs DoxR leads transcriptional and, more importantly, this correlates protection these apoptosis. Our demonstrate certain nonclassical activate upon prolonged “sneak” clinical relevance during course long-term chemotherapy.