BET-ting on Nrf2: How Nrf2 Signaling can Influence the Therapeutic Activities of BET Protein Inhibitors
BIOESSAYS
Authors: Chatterjee, Nirmalya; Bohmann, Dirk
Abstract
BET proteins such as Brd3 and Brd4 are chromatin-associated factors, which control gene expression programs that promote inflammation and cancer. The Nrf2 transcription factor is a master regulator of genes that protect the organism against xenobiotic attack and oxidative stress. Nrf2 has demonstrated anti-inflammatory activity and can support cancer cell malignancy. This review describes the discovery, mechanism and biomedical implications of the regulatory interplay between Nrf2 and BET proteins. Both Nrf2 and BET proteins are established drug targets. Small molecules that either activate or suppress these proteins are currently tested in clinical trials. The crosstalk between Nrf2 and BET proteins may have important, and until now overlooked, implications for the therapeutic effects of these drugs. Based on the information covered in this review, it should be possible to design combinatorial treatment strategies for cancer and inflammatory diseases, which may improve the efficacy of targeting a Nrf2 or BET proteins individually.
Three calcium-sensitive genes, fus, brd3 and wdr5, are highly expressed in neural and renal territories during amphibian development
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Authors: Bibonne, A.; Neant, I.; Batut, J.; Leclerc, C.; Moreau, M.; Gilbert, T.
Abstract
Numerous Ca2+ signaling events have been associated with early development of vertebrate embryo, from fertilization to organogenesis. In Xenopus Iaevis, Ca2+ signals are key regulators in the earliest steps of the nervous system development. If neural determination is one of the best-characterized examples of the role of Ca2+ during embryogenesis, increasing literature supports a determining role of organogenesis and differentiation. In blastula the cells of the presumptive ectoderm (animal caps) are pluripotent and can be induced toward neural fate with an intracellular increase of free Ca2+ triggered by caffeine. To identify genes that are transcribed early upon Ca2+ stimuli and involved in neural determination, we have-constructed a subtractive cDNA library between neuralized and non-neuralized animal caps. Here we present the expression pattern of three new Ca2+-sensitive genes: fus (fused in sarcoma), brd3 (bromodomain containing 3) and wdr5 (WD repeat domain 5) as they all represent potential regulators of the transcriptional machinery. Using in situ hybridization we illustrated the spatial expression pattern of fus, brd3 and wdr5 during early developmental stages of Xenopus embryos. Strikingly, their domains of expression are not restricted to neural territories. They all share a specific expression throughout renal organogenesis which has been found to rely also on Ca2+ signaling. This therefore highlights the key function of Ca2+ target genes in specific territories during early development. We propose that Ca2+ signaling through modulation of fus, brd3 and wdr5 expressions can control the transcription machinery to achieve proper embryogenesis. This article is part of a Special Issue entitled: 12th European Symposium on Calcium. (C) 2012 Elsevier B.V. All rights reserved.