Dataset Information

Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Blood Malignancies.

ABSTRACT: Deubiquitinases are enzymes that remove ubiquitin moieties from the vast majority of cellular proteins, controlling their stability, interactions, and localization. The expression and activity of deubiquitinases are critical for physiology and can go awry in various diseases, including cancer. Based on recent findings in human blood cancers, we discuss the functions of selected deubiquitinases in acute leukemia and efforts to target these enzymes with the aim of blocking leukemia growth and improving disease outcomes. We focus on the emergence of the newest generation of preclinical inhibitors by discussing their modes of inhibition and their effects on leukemia biology.

SUBMITTER: Gutierrez-Diaz BT

PROVIDER: S-EPMC7258259 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Blood Malignancies.

Gutierrez-Diaz Blanca T BT Gu Wei W Ntziachristos Panagiotis P

Trends in immunology 20200302 4

Deubiquitinases are enzymes that remove ubiquitin moieties from the vast majority of cellular proteins, controlling their stability, interactions, and localization. The expression and activity of deubiquitinases are critical for physiology and can go awry in various diseases, including cancer. Based on recent findings in human blood cancers, we discuss the functions of selected deubiquitinases in acute leukemia and efforts to target these enzymes with the aim of blocking leukemia growth and impr ...[more]

PMID: 32139316

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Project description:The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases-USP14, RPN11, and UCH37-are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome's conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context.

Dataset Information

Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Blood Malignancies.

Publications

Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Blood Malignancies.

Similar Datasets

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