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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
An alternative approach is downregulation of the target protein, which should have a potential therapeutic effect. Recently, we and others have developed a protein knockdown technology that induces degradation of target proteins using hybrid small molecules named SNIPERs [specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein erasers] or PROTACs (proteolysis targeting chimeras). They are chimeric molecules consisting of two different ligands connected by a linker. One ligand is for the target protein, while the other is for E3 ubiquitin ligases. Accordingly, these molecules are expected to crosslink the target protein and E3 ubiquitin ligases in cells, resulting in ubiquitylation and subsequent degradation of the target protein via the ubiquitin-proteasome system (UPS) (Fig. 16.1). In this chapter, we present examples of drugs that act by degrading oncogenic proteins, and discuss the features and prospect of chemical degraders.
Proteins and proteomics
Published in Firdos Alam Khan, Biotechnology Fundamentals, 2018
Ubiquitin is a small protein that can be affixed to certain protein substrates by enzymes called E3 ubiquitin ligases. Determining which proteins are poly-ubiquitinated can be helpful in understanding how protein pathways are regulated. This is, therefore, an additional legitimate “proteomic” study. Similarly, once it is determined what substrates are ubiquitinated by each ligase, determining the set of ligases expressed in a particular cell type will be helpful.
Proteins and Proteomics
Published in Firdos Alam Khan, Biotechnology Fundamentals, 2020
Ubiquitin is a small protein that can be affixed to certain protein substrates by enzymes called E3 ubiquitin ligases. Determining which proteins are poly-ubiquitinated can clarify how protein pathways are regulated. This is therefore an additional legitimate “proteomic” study. Similarly, once it is determined what substrates are ubiquitinated by each ligase, determining the set of ligases expressed in a specific cell type will be helpful.
Effects of tobacco compound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on the expression of epigenetically regulated genes in lung carcinogenesis
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Sun Woo Jin, Jong Seung Im, Jae Hyeon Park, Hyung Gyun Kim, Gi Ho Lee, Se Jong Kim, Seung Jun Kwack, Kyu-Bong Kim, Kyu Hyuck Chung, Byung Mu Lee, Sam Kacew, Hye Gwang Jeong, Hyung Sik Kim
MDM2 is an E3 ubiquitin ligase that encodes a negative regulator of the p53 tumor suppressor (Oliner et al. 1992). MDM2 binds to the transcriptional activation domain of p53 to regulate stabilization and activation of p53 (Haupt et al. 1997; Weber et al. 1999). MDM2 overexpression, in particular, was implicated in several tumors, including sarcoma, colon cancer, and gastric cancer (Embade et al. 2012; Oliner, Saiki, and Caenepeel 2016). Previous investigators demonstrated that MDM2 is an optimal therapeutic target in tumors carrying wild-type tumor protein 53 (Burgess et al. 2016; Imanishi et al. 2019; Pellegrino et al. 2015). MDM2 overexpression in fibroblasts enhanced cancer cell invasion and growth of inoculated tumors in mice. Epigenetic modifications, including aberrant DNA methylation, are critical events in carcinogenesis occurrence (Baylin and Ohm 2006). MDM2 might regulate the target proteins interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα), which play an important role in regulating the mitogen-activated protein kinase (MAPK) and NF-κB pathways.
The roles of membrane transporters in arsenic uptake, translocation and detoxification in plants
Published in Critical Reviews in Environmental Science and Technology, 2021
Protein-protein interactions also play a role in regulating the functional activities of As transporters. It has been reported that the Ca-dependent protein kinase AtCPK31 is a positive-regulator for As(III) uptake through interacting with AtNIP1;1 in Arabidopsis (Ji et al., 2017). AtCPK31 and AtNIP1;1 are co-expressed in the roots and physically interact at the plasma membrane. Knocking out AtCPK31 leads to decreased As accumulation and enhanced As(III) tolerance. These phenotypes are similar to those in the AtNIP1;1 mutants. In contrast, plants with elevated expression of AtCPK31 are more sensitive to As(III) than the wild type plants (Ji et al., 2017). However, the mechanism by which AtCPK31 regulates the transport activity of AtNIP1;1 remains unclear. The rice OsNLA1, a RING‐type ubiquitin ligase, is a plasma membrane localized protein that physically interacts with OsPHT1;2 and OsPHT1;8, resulting in increased degradation of phosphate transporters (Yang et al., 2017; Yue et al., 2017; Zhong et al., 2017). Mutation of OsNLA1 resulted in the accumulation of OsPHT1;8 protein with the consequence of increased As accumulation in roots and shoots (Xie et al., 2019).
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.