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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].
Chemical Causes of Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Gary M. Williams, Alan M. Jeffrey
As noted above, neoplastic cells display abnormalities in repair systems, including mismatch repair (33), AGAT (33), BRCA1 function in double-strand break repair (343), and DNA polymerase β (49). Recently, the HR6B (human homolog of yeast Rad6) DNA repair gene, which encodes ubiquitin-conjugating enzymes (E2), has been reported to be overexpressed in breast cancers, leading to genetic instability (344).
High-throughput tool to discriminate effects of NMs (Cu-NPs, Cu-nanowires, CuNO3, and Cu salt aged): transcriptomics in Enchytraeus crypticus
Published in Nanotoxicology, 2018
Susana I. L. Gomes, Carlos P. Roca, Natália Pegoraro, Tito Trindade, Janeck J. Scott-Fordsmand, Mónica J. B. Amorim
Also affected by Cu-Nwires and Cu salt-aged are the histone modifications: histone ubiquitination and histone H3 acetylation. Histone ubiquitination is being induced by the up-regulation of several transcripts (e.g. ubiquitin-conjugating enzyme e2a, ubiquitin-conjugating enzyme e2n). The involvement of E2 ubiquitin conjugating enzyme family suggests the implication in DNA damage repair (Cao and Yan 2012), which was found triggered by Cu independently of its form (see discussion above). Histone H3 acetylation is a known epigenetic marker associated with gene regulation (Yan and Boyd 2006). Decrease in histone acetylation has been associated with nickel carcinogenesis (Arita and Costa 2009), however, our current results indicate increase in histone H3 acetylation in response to Cu (Nwires and salt-aged). Again, the investigation of longer-term effects of Cu, including multi-generational should be pursued.
TDP-43 post-translational modifications in health and disease
Published in Expert Opinion on Therapeutic Targets, 2018
At the protein level, the enzymes responsible for TDP-43 ubiquitination have been initially identified from mass-spec analysis of TDP-43 interactors. Using this approach, it was found that the UBE2E class of ubiquitin-conjugating enzymes was able to promote TDP-43 ubiquitinylation whereas UBPY reduced it [182]. Using a variety of transgenic and lentiviral experimental approaches, another enzyme that has been shown to ubiquitinate TDP-43 is Parkin, an E3 ubiquitin ligase [183]. Ubiquitination of TDP-43 by Parkin facilitates its accumulation in the cytoplasm in a multiprotein complex with HDAC6. Interestingly, TDP-43 expression can increase the levels of Parkin mRNA and protein levels, suggesting the existence of a protective mechanism to remove excess TDP-43 protein from the nucleus [183].
When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies
Published in Expert Review of Proteomics, 2018
Julie A. Reisz, Alexander S. Barrett, Travis Nemkov, Kirk C. Hansen, Angelo D’Alessandro
The UPS aids in the homeostasis of short-lived cellular peptides and proteins by tagging damaged proteins with one or more ubiquitin molecules (76 amino acids) at lysine residues, then transporting labeled proteins to the 26S proteasome for degradation. Conjugation of ubiquitin moieties to protein lysines occurs in a step-wise ATP-dependent fashion facilitated by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2), and ubiquitin-ligating (E3) enzymes. There exist distinct proteasome forms that demonstrate preference for metabolizing mildly oxidized proteins or ubiquitinated proteins [57]. Critically, the ubiquitination process and proteasome function are both ATP dependent. Moreover, oxidation can inhibit ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) via modification (e.g. glutathionylation, nitrosation) of active site cysteine residues along with noted negative impacts on proteasome function [57]. The UPS is critical for homeostasis maintenance in a variety of cell types and helps to preserve cell vitality by degrading proteins of the apoptotic machinery when they are not needed [58]. UPS activity is increased in stem cells (reviewed in [59]), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) as a strategy of preserving plasticity. Recently, several E3 ubiquitin ligases were identified as elevated in hESCs compared to differentiated cells as one of the possible mechanisms underlying enhanced UPS [60]. In the event of severe or prolonged cellular stress, the capacity of the UPS to clear ubiquitinated proteins can be exceeded. In such cases, these proteins are directed to autophagy.