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Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
Cullin RING E3 ubiquitin ligases (CRLs) are multi-subunit complexes that catalyze the transfer of ubiquitin to specific substrate proteins. The complex of cullin1 (CUL1), S-phase kinase associated protein 1 (SKP1), and mammalian F-box protein β-transducin repeat-containing protein (β-TRCP) is a CRL known as CRL1β-TRCP. The β-TRCP of CRL1β-TRCP binds to IκBα and promotes its ubiquitination and degradation (Yaron et al., 1998). A 10 amino acid phosphopeptide segment of IκBα is both necessary and sufficient to mediate its binding to CRL1β-TRCP and subsequent ubiquitination and degradation (Yaron et al., 1997; Yaron et al., 1998). Dr. Deshaies’ and Crews’ groups designed and synthesized a series of hybrid molecules named PROTACs consisting of the IκBα phosphopeptide and a ligand of target proteins such as methionine aminopeptidase 2 (Sakamoto et al., 2001), ERα, and AR (Sakamoto et al., 2003). Although the β-TRCP-recruiting PROTACs induce ubiquitination and degradation of target proteins in vitro, they have low activity in cells, presumably because of the poor cell permeability of the employed peptide. To overcome this problem, the IκBα phosphopeptide was replaced by a hydroxyproline-containing pentapeptide from hypoxia-inducible factor a (HIF-1a), which is recognized by von Hippel-Lindau (VHL). VHL is a substrate recognition component of an E3 ubiquitin ligase complex containing cullin 2 (CUL2), RING-box protein 1 (RBX1), elongin B (ELOB), and elongin C (ELOC). The CUL2-RBX1-ELOB-ELOC-VHL complex (known as CRL2VHL) directs the ubiquitylation and subsequent proteasomal degradation of HIF-1a under normoxic conditions. VHL-recruiting PROTACs, consisting of the HIF-1a pentapeptide and a ligand of ERα or AR, are cell permeable and induce significant degradation of ERα and AR at 12.5 and 50 μM, respectively (Rodriguez-Gonzalez et al., 2008).
Protective effects of natural compounds against paraquat-induced pulmonary toxicity: the role of the Nrf2/ARE signaling pathway
Published in International Journal of Environmental Health Research, 2023
Hasan Badibostan, Nastaran Eizadi-Mood, A. Wallace Hayes, Gholamreza Karimi
Under normal conditions, Nrf2 is continuously degraded through the Keap1/Cul3-Rbx1 complex (Kaspar et al. 2009). Keap1 functions as a substrate adaptor to link Nrf2 to Cullin 3 (Cul3) and Ring box protein 1 (Rbx1). There is an autoregulatory loop between Nrf2 and Cul3-Rbx1 that determines their cellular levels. Following activation, the level of Nrf2 rises, and nuclear Nrf2 heterodimerizes with one of the small Maf proteins. These Nrf2–Maf heterodimers recognize antioxidant response elements (AREs) and enhance the expression of antioxidant genes (Audousset et al. 2021).
Xenobiotic metabolism and transport in Caenorhabditis elegans
Published in Journal of Toxicology and Environmental Health, Part B, 2021
Jessica H. Hartman, Samuel J. Widmayer, Christina M. Bergemann, Dillon E. King, Katherine S. Morton, Riccardo F. Romersi, Laura E. Jameson, Maxwell C. K. Leung, Erik C. Andersen, Stefan Taubert, Joel N. Meyer
SKN-1 is a TF that belongs to the basic leucine zipper (bZIP) family of TFs that regulates stress response pathways across species (Blackwell et al. 2015). In C. elegans, SKN-1 is especially important for oxidative stress and starvation adaptation and is induced by complex regulatory pathways involving MAPK and insulin signaling as well as negative regulation by the WDR-23 protein, which appears to promote SKN-1 for degradation, an inhibitory response that is alleviated by oxidative stress (Blackwell et al. 2015). In addition to its role as an antioxidant regulator, SKN-1 also plays important roles in xenobiotic detoxification. Specifically, skn-1 loss sensitizes worms to the common benzimidazole albendazole, and skn-1 gain-of-function mutations increase tolerance to this drug. skn-1 regulated genes include albendazole induced cyp, gst, and ugt genes, of which ugt-22 loss also enhances albendazole efficacy (Fontaine and Choe 2018). Similarly, induction of phase I and II detoxification genes by acrylamide also requires skn-1, at least in part, and unbiased genetic screens for genes involved in stimulation of gst genes by acrylamide identified known components of the SKN-1 pathway, including the negative regulator wdr-23, and the metabolic enzyme alh-6 (Fukushige et al. 2017; Hasegawa and Miwa 2010). The Skp1 homologs skr-1/2, components of Skp-Cullin-F box ubiquitin ligase (SCF) complexes that regulate SKN-1, are also essential for the SKN-1 detoxification response to acrylamide (Wu et al. 2016). The regulation of SKN-1 during xenobiotic stress is thus apparently similar as that seen in oxidative stress, involving derepression from WDR-23 and SKR-1/2 mediated degradation. How xenobiotic molecules act to relieve WDR-23 action on SKN-1 is not known at this time, but the effects of skr-1/2 are notably independent of classical stress activated MAPK signaling, implicating alternative pathways. Indeed, SKN-1 activity is highly regulated, and studies on its activity in oxidative stress conditions revealed numerous novel regulators (Crook-McMahon et al. 2014). It would be interesting to test whether any of these factors are necessary for elevated SKN-1 activity in response to xenobiotic exposure.