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CBL Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Through its E3 ubiquitin ligase activity, the CBL protein mediates the transfer of ubiquitin from ubiquitin-conjugating enzymes (E2) to specific substrates, and interacts with and promotes tyrosine-phosphorylated substrates for proteasome degradation and ubiquitination. In experimental knockout mice, removal of the CBL gene prolongs activation of tyrosine kinases after cytokine stimulation, enhances sensitivity to hematopoietic growth factors, and expands hematopoietic stem cell pool and myeloproliferative features [16,17].
Ascorbate and the Hypoxic Response in Cancer
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Christina Wohlrab, Caroline Kuiper, Gabi U. Dachs
The proline hydroxylases (PHD1–3) target two prolines in the oxygen-dependent degradation domains of the HIF-α subunit (P402 and P564 of HIF-1α; P405 and P531 of HIF-2α) [57,62]. Hydroxylation of these amino acids enables binding of the VHL-E3 ubiquitin ligase complex and targets it for polyubiquitylation and proteasomal degradation (Figure 4.2). PHD2 is the dominant enzyme for hydroxylation of HIF-1α, and PHD1 and PHD3 have more influence on HIF-2α [63]. Hydroxylation of an asparagine in the CAD (N803 of HIF-1α, N847 of HIF-2α) by factor inhibiting HIF (FIH) disrupts recruitment of the coactivator CBP/p300, which interferes with the transactivation activity of HIF [60]. FIH has a higher affinity for oxygen reflected by a lower Km value (90 μM) than PHDs (230–250 μM) and remains active at mild hypoxia, which means it can reduce the transcriptional activity of HIF even in conditions where HIF protein is stabilized [64–66]. Of the two HIF isoforms, HIF-1α has been shown to be more sensitive than HIF-2α to regulation by FIH [67].
REGULATORY MECHANISMS
Published in David M. Gibson, Robert A. Harris, Metabolic Regulation in Mammals, 2001
David M. Gibson, Robert A. Harris
Of increasing importance is the ubiquitin-protcasomc degradativc system which stereospecificallv targets many rapidlv turning over proteins, llhiquitin, a small molecular weight (8.5kDa), highly conserved protein, is activated first by ATP (similar to the formation of fatty acyl-CoA thiol esters) before it is transferred, stepwise, to a target protein. The first thiol ester transfer is from the protein El to E2 which is the ubiquitin donor. The third component, E3, ubiquitm ligase, fingers a specific cognate proteolytic substrate by the covalent attachment of activated uhiquitins to terminal amino groups of lysine siile chains. There are many kinds of ubiquitin ligases each of which recognize specific sequences of amino acids on the target proteins, for example one ligase class has an SI 12 domain (Table 3.2) that recognizes a tyrosine-phosphorylatcd protein target, llhiquinatcd proteins are processed by p rot caso m es, giant (2,500kl)a) barrel-shaped multiprotcin complexes which hvdrolyze ubiquitin-tagged proteins by an ATP-dependent process in which ubiquitin is released for further employment. The ubiquitin-protcasóme system provides a mechanism for controlling the levels of proteins instrumental in the progression of the cell cycle, in cell differentiation and lor removal of misfolded proteins.
Enhanced antitumor activity induced by a DNA vaccine encoding E7 antigen fused to an ERAD-targeting sequence
Published in Journal of Drug Targeting, 2023
David Hernán Martínez-Puente, Rodolfo Garza-Morales, José Juan Pérez-Trujillo, Federico Bernabé-Acosta, Arnulfo Villanueva-Olivo, Aracely García-García, Laura Mireya Zavala-Flores, Humberto Rodríguez-Rocha, Jesús Valdés, Odila Saucedo-Cárdenas, Roberto Montes de Oca-Luna, María de Jesús Loera-Arias
In the present study, the expression of proteins that contained the membrane-binding domain (COX2-E7 and SP-MBD-E7-ERAD-K) was not affected by the presence of the MG132 proteasome inhibitor. At the same time, the expression of proteins that did not contain the MBD (SP-E7-ERAD-K and SP-E7-ERAD-S) was enhanced, indicating that the degradation of COX-2 is proteasome-dependent (Figure 3). This finding suggests the use of different degradation pathways that depend on the presence of the membrane-binding domain. In yeasts, it has been reported that there are three types of degradation by the ERAD pathway depending on the nature of the proteins as follows: ERAD-L for ER lumen proteins, ERAD-M for transmembrane proteins, and ERAD-C for cytosolic proteins. These pathways are differentiated by the ubiquitin ligases that directly degrade these proteins. However, there are fewer studies on the types of degradation by the ERAD pathway in mammalian cells [55].
Targeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints
Published in International Journal of Radiation Biology, 2021
Jessica M. Molkentine, David P. Molkentine, Kathleen A. Bridges, Tongxin Xie, Liangpeng Yang, Aakash Sheth, Timothy P. Heffernan, David A. Clump, Alma Z. Faust, Robert L. Ferris, Jeffrey N. Myers, Mitchell J. Frederick, Kathryn A. Mason, Raymond E. Meyn, Curtis R. Pickering, Heath D. Skinner
p16 is known to be overexpressed in HPV(+) cancers and is a surrogate marker of HPV status (El-Naggar and Westra 2012; Stephen et al. 2013). We previously established that p16 regulates ubiquitin-dependent homologous DNA repair by down-regulating a key E3 ubiquitin ligase TRIP12, which is needed for efficient BRCA1 dependent DNA repair. TRIP12 was found to have higher basal level expression in HPV(−) than HPV(+) cell lines, and when TRIP12 was knocked down directly with siRNA in HPV(−) cells, BRCA1 foci formation was reduced leading to a more radiosensitive phenotype (Wang, Zhang, et al. 2017). Since PARP inhibitors have been shown to be more effective as single agents in tumors deficient in HR (Farmer et al. 2005; McCabe et al. 2005; McCabe et al. 2006), we had previously expected that HPV(+) cell lines would also respond better to PARP inhibition due to their reduced BRCA1 expression. However, based on our in vivo screening data and in vitro validation data we wished to explore this question in more detail.
A patent review of discoidin domain receptor 1 (DDR1) modulators (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Particularly, allosteric inhibitors targeting the extracellular domain could be considered as a new approach to specifically modulate DDR1-mediated downstream signaling. Since extracellular regions of DDR1 and DDR2 bind different collagens and share a relatively low degree of sequence identity, highly specific DDR1 or DDR2 inhibition might be achieved by utilizing this strategy. Encouragingly, a small-molecule allosteric regulator targeting the extracellular domain of DDR2 was recently discovered to exhibit good target specificity which paved a solid foundation for the discovery of new generation DDR1 inhibitors with improved target specificity [69]. PROTACs or heterobifunctional degrader molecules typically comprise an E3 ligase binding scaffold (hereafter E3-moiety), attached through a linker to another small molecule (hereafter target-moiety) that binds a target protein of interest. Recruitment of this target protein to the E3 ubiquitin ligase facilitates ubiquitination and subsequent degradation of the target protein. PROTACs represent a promising new pharmacologic modality now widely explored in chemical biology and drug discovery. The PROTAC technique can be applied in the development of DDR1 modulators, which would open a new window for targeted DDR1 therapies. The monoclonal antibody binds to a specific antigen on the cancer cell. The main advantage of antibody over kinase inhibitors is higher selectivity and safety.