Uncapping NF-κB activity in pancreatic cancer.

Living cells must be capable of rapidly responding to intrinsic and environmental cues to ensure normal development and homeostasis. The NF-jB transcription factor mediates a series of such rapid-response programs, serving as a master regulator of gene transcription in cells subjected to inflammation, irradiation, or other stress states (Karin, 2009). While cells must be able to rapidly respond to NF-jB stimuli, it is similarly important to restrain sustained high NF-jB levels that can trigger chronic inflammation or cellular transformation. Results published by Lu et al (2011) in this issue of The EMBO Journal identify a novel mechanism that amplifies NF-jB activity; NF-jB upregulates mir301a, a microRNA (miRNA) that itself blocks the expression of an NF-jB inhibitor. The resulting positive feedback mechanism potentiates NF-jB target gene expression. While this pathway may be important for normal cellular stress responses, the authors show that its sustained induction in pancreatic cancer cells leads to constitutive NF-jB activity that drives tumour progression. NF-kB is largely regulated at the level of protein stability via a well-characterized kinase cascade that controls the targeting of this transcription factor to the proteasome (Karin, 2009). However, acute adaption to cellular stresses requires additional inputs that ensure rapid and potent NF-kB target gene regulation. Conversely, tight controls are needed to restrain the dangerous pro-inflammatory and transforming functions of elevated NF-kB signalling. Positive and negative feedback signalling networks are recurring themes in biology to achieve such regulation. Recent studies identified a major role of miRNAs as components of feedback signalling networks, as emphasized for NF-kB by Lu et al (2011). The authors sought to identify miRNAs that target the NF-kB pathway, with a particular focus on identifying candidates that activate NF-kB-mediated transcription. miRNAs (or miRs) are an evolutionarily conserved class of non-coding double-stranded RNA molecules that suppress expression of their target genes by imperfect binding to the 30UTR of target mRNA, leading to either blocked translation or degradation of the message (Garzon et al, 2010). Using an miRNA library screen based on a luciferase reporter, they identify miR301a as a striking activator of NF-kB. In silico approaches predict numerous putative targets of miR301a, including the known NF-kB-regulator Nkrf. Nkrf represses NF-kB transcriptional