Feed-Forward and Feed-Back Circuits of the NRF2/AP-1 Composite Pathway

Abstract

Being the central regulator of oxidative status of the cell, NRF2 must be regulated so that its activity can be rapidly and strongly induced when needed and quickly suppressed when not. Moreover, for the cell, NRF2 means much more than just antioxidant defense. Numerous general functions rely on NRF2 and related factors. All this implies that the NRF2 pathway has peculiar and powerful mechanisms of control of its activity. To a great extent, these mechanisms are based on feed-forward and feedback circuits. These circuits, more than a dozen, are in the focus of this chapter.intriguing since central proteasomal [2], autophagic [3], general signaling [4,5], and, moreover, cell proliferation, cell cycle and survival regulation factors [1] are in fact NRF2 targets.Although 645 of the 1055 Nrf2 target genes were found to have basal type of expression regulation by this factor [1], Nrf2 is still required to be present in the nucleus in significant amounts to drive their expression. Notably, most of these genes are not at all related to antioxidant and xenobiotic defense systems, i.e., they are essential for proliferation and basic functioning of the cell. Thus, basal expression driven by NRF2 is important for the cell, but to what extent? One should bear in mind that NRF2 knockouts are nonlethal and generally appear normal in stable laboratory conditions [6], yet they are susceptible to numerous diseases [7-9], especially when the housing conditions are suboptimal [6,[10][11][12]. This confirms that basal NRF2 functioning, although not vital, is critical for the cell and organism even when no pro-oxidant or xenobiotic exposure is present.It implies that some cellular mechanisms serve to provide the cell with at least minimal necessary NRF2 activity. On the other hand, it is inherently important for an inducible antioxidant and xenobiotic defense pathway to act as quickly as possible, thus signal amplification is required whenever the initial stimulus is applied. These two distinct prerequisites for normal cell functioning in ever-changing environment appear to be resolved in principle similarly: there are feed-forward circuits that maintain steady-state level of the NRF2 activity and make signal amplification possible when fast cellular reactions are required.Conversely, too much NRF2 activity is no better than its absence: Keap1-null mice demonstrate postnatal lethality [13,14], an effect coinciding with nuclear Nrf2 localization [14] and reversed by Nrf2 downregulation [13]. In this case, several feed-back circuits protect the cell and organism from obsessive NRF2 activation.Most of the feed-forward and feed-back circuits of the NRF2 pathway also involve the closely related transcription factor activator protein 1 (AP-1) represented by homodimers of Jun proteins (JUN, JUNB, JUND) or heterodimers of Fos (FOS, FOSB, FOSL1, FOSL2) and Jun proteins. There are also other dimers of Jun/Fos proteins-e.g. with Atf-proteins [15-17]-still referred to as AP-1 complexes (although either Jun or Fos proteins are absent), and oligom...

Pros and cons of NRF2 activation as adjunctive therapy in rheumatoid arthritis

“…This particular feature of the TRE and ARE binding sites can drive either a positive or a negative crosstalk between AP1 and NRF2 when working on the same ARE with embedded TRE, and is also responsible for the reciprocal regulation of gene expression in a cell-dependent context. Zolotukhin and Belanova hypothesized [164] that, when JUN proteins stimulate NRF2 expression, the subsequently increased production of TRX promotes JUN binding to DNA by creating a reductive microenvironment. Such a feed-forward loop gives arguments that AP1-driven inflammation can trigger the activation of the NRF2 pathway which, through a feed-forward loop, will further promote inflammation by enhancing the DNA-binding capacity of inflammatory transcription factors.…”

Oxidative Status Pathways: Systemic Biomarkers

“…Human oxidative status pathways are rich in signal amplification and autoregulatory blocking circuits. In one of our previous works, we discussed 15 such experimentally proven circuits of just one of the pathways -the NFE2L2/AP-1 pathway [10].…”

“…In contrast, complex pathways contain signal amplification circuits, demonstrate delayed and sustained changes in cellular parameters and, moreover, interact with other pathways (i.e. respond in dependence of cellular signaling background), thus providing a researcher with a plethora of data characterized by high signal-to-noise ratio and high informativeness [10]. Superior informativeness of complex signaling pathways renders them highly promising for clinical applications.…”