Regulatory potential for concerted modulation of Nrf2- and Nfkb1-mediated gene expression in inflammation and carcinogenesis

Abstract

Many studies have implicated nuclear factor E2-related factor 2 (Nrf2) and nuclear factor-kB1 (Nfkb1) in inflammation and cancer. However, the regulatory potential for crosstalk between these two important transcription factors in inflammation and carcinogenesis has not been explored. To delineate conserved transcription factor-binding site signatures, we performed bioinformatic analyses on the promoter regions of human and murine Nrf2 and Nfkb1. We performed multiple sequence alignment of Nrf2 and Nfkb1 genes in five mammalian species -human, chimpanzee, dog, mouse and rat -to explore conserved biological features. We constructed a canonical regulatory network for concerted modulation of Nrf2 and Nfkb1 involving several members of the mitogen-activated protein kinase (MAPK) family and present a putative model for concerted modulation of Nrf2 and Nfkb1 in inflammation/ carcinogenesis. Our results reflect potential for putative crosstalk between Nrf2 and Nfkb1 modulated through the MAPK cascade that may influence inflammation-associated etiopathogenesis of cancer. Taken together, the elucidation of potential relationships between Nrf2 and Nfkb1 may help to better understand transcriptional regulation, as well as transcription factor networks, associated with the etiopathogenesis of inflammation and cancer.

Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (Nrf2)

“…Moreover, a close relation of enhanced Nrf2 activation and higher NF-kB activity was detectable in a line of tissue samples from colon cancer patients (Supplementary Figure 2). Thus, even though inhibitory interferences between Nrf2 and NF-kB have also been reported (Liu et al, 2008;Song et al, 2009), our findings point to a stimulatory interference reflecting a complex crosstalk of these transcription factors in carcinogenesis (Nair et al, 2008).…”

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

“…DMF treatment, especially at 30 mg/kg, restored COX-2 and Il-1b to baseline levels, highlighting the role of DMF in moderating neuronal cell damage under these conditions by forming excessive amounts of harmful prostanoids and free radicals (50). Recent findings have also linked activation of the Nrf-2 system to anti-inflammatory effects, and they may also be involved via interactions with NF-jB (49). The relationship between Nrf-2 and NF-jB is not well characterized, but the identification of NF-jB binding cites in the promoter region of the Nrf-2 gene suggests cross-talk between these two regulators of inflammatory processes.…”

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

“…Nuclear factor kappa B is a negative regulator of NRF2 by binding to response elements in the NRF2 gene promoter [36]. In addition, the p65 subunit blocks NRF2 binding to CREB protein and recruits histone deacetylase 3, a co-repressor of ARE [37].…”