China
Africa
Explore chapters and articles related to this topic
PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alicja M. Gruszkaa, Myriam Alcalay
It was first thought that the profound curative effect originated from ATRA’s ability to reverse transcriptional repression of genes responsible for myeloid differentiation. However, ATRA induces a proteasome- and caspase-mediated degradation of the oncogene as an additional effect. A kinetics analysis shows that ATRA causes a biphasic PML/RARa degradation. A rapid decrease in PML/RARa expression is observed already within 1 h, whereas a second degradative step occurs after 12 h and is characterised by the appearance of an 85-kDa PML/RARa cleavage product (APML/RARa). Not surprisingly, the ligand-binding domain required for transcriptional activation in also required for the receptor catabolism, as a way of turning off transcription factors following activation [65]. Interestingly, UBE2D3 ubiquitin-conjugated and UBE1L ubiquitin-activating enzymes are both ATRA-induced [14]. Specifically, proteasome-mediated degradation depends on the binding of SUG1 proteasome subunit to the AF-2 transactivation domain of RARa [59]. Clearly, the degradation of the oncogene leads to the de-repression of the non-RARE sites as well as to the liberation of the proteins sequestered within complexes with PML/RARa. It has to be pointed out that the relative contribution of the two mechanisms, transcriptional re-activation and protein destruction to the therapeutic effect of ATRA remains controversial [34] (Fig. 10.1).
Gene Expression Profiling to Detect New Treatment Targets in Leukemia and Lymphoma: A Future Perspective
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Torsten Haferlach, Wolfgang Kern, Alexander Kohlmann
Another structure identified by gene expression profiling is the ubiquitin-activating enzyme E1-like (UBE1) gene that is induced by all-trans retinoic acid (ATRA) in NB4 cells (24). Detailed investigation revealed that ATRA activates the UBE1 promoter and the overexpression of UBE1 therefore triggers the degradation of promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) and leads to apoptosis in acute promyelocytic leukemia (APL) cells (25). Clinical studies with UBE1 in leukemia are however missing.
Golgi apparatus regulation of differentiation
Published in C. Yan Cheng, Spermatogenesis, 2018
Louis Hermo, Regiana L. Oliveira, Charles E. Smith, Catherine E. Au, John J. M. Bergeron
Autophagy-related gene 7 (Atg7) is homologous to the ubiquitin-activating enzyme E1 (Uba1) and encodes the E1-like enzyme that is essential to the ubiquitin conjugation system. Germ cell specific Atg7-knockout mice are infertile due to a defect in acrosome biogenesis. Atg7 partially regulates GOPC during acrosome biogenesis. Proacrosomic vesicles fail to fuse into a single acrosomal vesicle during the Golgi phase of early spermatids.160
Prognostic Value and Molecular Mechanisms of Proteasome 26S Subunit, Non-ATPase Family Genes for Pancreatic Ductal Adenocarcinoma Patients after Pancreaticoduodenectomy
Published in Journal of Investigative Surgery, 2022
Caifu Zhou, Haixia Li, Xiao Han, Hongbing Pang, Manya Wu, Yanping Tang, Xiaoling Luo
In this research, GO function and KEGG pathway analyses revealed that PSMDs primarily played a part in the UPS and via adjusting the proteasome activity to achieve physiological functions [13]. In UPS, ubiquitination represented an enzymatic cascade mediated by E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligation enzymes) [78,79]. On the one hand, UPS was involved in protein degradation as mentioned above, on the other, it was also responsible for regulating some biological processes (e.g., DNA repair, linkages in the nuclear factor-κB [NF-κB] pathway) [80]. As for E3, the progress of degrading cell cycle regulators was promoted by enzymes such as SCF (Skp1-cullin1-F-box) and the APC/C [81]. UPS also plays a role in regulating cell cycle, which is in agreement with our GSEA results. Proteasome inhibitors have succeeded in MM and an inhibitor of ubiquitin activating enzyme for cancer treatment has been under study [82,83]. PSMDs were crucial genes that affect these tumor-related biological processes. There was a report that the PSMD11 protein induced rapid synthesis by activating the MEK1/ERK1/2 signaling pathway in PC cells, and finally regulated the acute apoptosis of PC cells [84]. However, the potential mechanism of PSMDs in PC remains unclear and further research is required.
Targeting protein clearance pathways in GBA1-associated Parkinson disease
Published in Expert Opinion on Therapeutic Targets, 2022
Chase Chen, Ellen Hertz, Yu Chen, Ellen Sidransky
The UPS is a selective proteolytic system that regulates protein degradation in eukaryotic organisms. The covalent attachment of ubiquitin, a small 76-amino acid protein, to lysine residues of proteins through the cascade of three enzymes (E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin ligase) targets proteins for degradation by the proteasome. Mutations in the gene encoding Parkin (PRKN), a well-studied E3 ubiquitin ligase, impair degradation of damaged mitochondria (mitophagy) and result in familial forms of PD. (1) Targeted protein degradation
Current perspectives on the treatment of double hit lymphoma
Published in Expert Review of Hematology, 2019
Lin-Rong Li, Liang Wang, Ying-Zhi He, Ken H. Young
Disturbed ubiquitin-proteasome signaling resulted in myc overexpression, sensitized DHL cells to ubiquitin-activating enzyme (UAE) inhibition and stress-mediated apoptosis [63]. Proteasome inhibitor bortezomib plus R-CHOP suggested a positive effect in the molecular high-grade DLBCL subgroups defined by gene expression [21]. In the context of targeting upstream regulators of myc, the mTOR inhibitor MLN0128 and everolimus both exhibited pronounced activities against myc-dependent lymphoma, that might because mTOR functioned in the survival of myc-driven cells via substrate 4E binding protein-1 [64,65]. GSK-3β (downstream target of mTOR and upstream regulator of c-myc) inhibitor 9-ING-41, both as a single agent and in combination with venetoclax, idelalisib (PI3K inhibitor) and BAY-1143572 (CDK-9 inhibitor), showed antineoplastic effects against a DHL cell line [66]. Targeting HDAC and PI3K inhibition with the dual-acting inhibitor CUDC-907 (fimepinostat) was also efficient [67]. In the context of targeting myc downstream signaling, since c-myc upregulated Aurora A and B both directly and indirectly, and that Aurora A stabilized N-myc by either interacting with N-myc or counteracting the SCF ubiquitin ligase, Aurora kinases thereby arose as attractive therapeutic targets for myc-expressing lymphomas [68,69]. Selective Aurora A kinase inhibitor alisertib demonstrated efficacy in 2 patients with double-hit features, according to the results from a phase 2 study [70]. Importantly, alisertib and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib indicated significant synergy yet little single-agent efficacy in double-hit or double-espressor xenografts [71]. The activity of downstream target PLK-1 was upregulated by myc and linked with inferior prognosis. PLK-1 inhibitor volasertib, either alone or in combination with bcl-2 inhibitor venetoclax, was efficacious in killing DHL [72]. Synergetic exposure of DHL cell lines to volasertib, JQ-1 with HDAC inhibitor belinostat or vorinostat resulted in marked cell death [73,74].