1, 2 Accordingly, disturbed proteasomal degradation rates are causative for the development and progression of malignancies. 3, 4Ĭell cycle progression, proliferation, senescence, differentiation, apoptosis, and a multitude of other physiologically relevant functions are controlled by ubiquitinylation-dependent proteasomal degradation. 1, 2, 3 In contrast to poly-ubiquitinylation, mono-ubiquitinylation or ubiquitinylation linked via lysine-63 of ubiquitin rather modifies protein functions and interactions. Proteasome-associated deubiquitinylation and adenosine triphosphate-dependent translocation into the 20S core complex then leads to the cleavage of unfolded substrates by trypsin-, chymotrypsin- and caspase-like peptidases. 4 Covalent tagging of multiple ubiquitin polypeptides connected via lysine-48 allows the recognition of substrates by the 19S subunit of the proteasome.
1, 2 By interacting with defined sets of substrates and ubiquitin-conjugases, ubiquitin-ligases ensure the specificity of the UPS. E2 ubiquitin-conjugases then accept ubiquitin moieties to covalently attach them to E3 ubiquitin-ligases or to lysine residues in substrates bound by E3s.
4 After their activation by adenosine triphosphate, ubiquitin molecules (76 amino acids, ∼8.5 kDa) are transferred to E1 enzymes. 1, 2 It is controlled by the hierarchical actions of three classes of enzymes (E1-E2-E3), of which two E1s, >30 E2 ubiquitin-conjugases, and hundreds of E3 ubiquitin-ligases have been isolated from eukaryotic cells. The ubiquitin–proteasome system (UPS) is the main proteolytic system of eukaryotic cells. 1, 2, 3 This cellular balance is often referred to as a ‘yin-yang’ and unobstructed cellular functions are only achievable when harmonious. Homeostasis relies on a balance between de novo protein synthesis, protein modifications, and precise degradation of misfolded and potentially harmful proteins. In addition, our review highlights potential areas for future research on SIAH proteins. We also discuss that epigenetic drugs belonging to the group of histone deacetylase inhibitors induce SIAH-dependent proteasomal degradation to accelerate the turnover of leukemogenic proteins. Here, we summarize functions of SIAH ubiquitin-ligases in leukemias, how they select leukemia-relevant substrates for proteasomal degradation, and how the expression and activity of SIAH1 and SIAH2 can be modulated in vivo. However, the relevance and therapeutic potential of SIAH-dependent processes has not been fully elucidated. Increasing evidence accumulates that ubiquitin-ligases termed mammalian seven in absentia homologs (SIAHs) are not only critical for the pathogenesis of solid tumors but also for leukemogenesis. Therefore, pharmacological modulation of these proteins could allow a specific level of control. Ubiquitin-ligases selectively bind substrates to target them for poly-ubiquitinylation and proteasomal degradation. As dysregulation of the UPS is observed in most cancers including leukemia, the UPS is a valid target for therapeutic intervention strategies. The ubiquitin–proteasome system (UPS) is a major pathway for the proteolytic degradation of cellular proteins. Proteases act in an irreversible manner and therefore have to be strictly regulated. The delicate balance between the synthesis and the degradation of proteins ensures cellular homeostasis.
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