The role of ubiquitination in tumorigenesis and targeted drug discovery
By Lu Deng, T. Meng, Lei Chen, Wenyi Wei, Ping Wang. Signal Transduction and Targeted Therapy, 2020
656 citations recorded by the source corpus.
Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the “quantity” and “quality” of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI‐219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/4f6ff7fc7369a00b7a0eafc79123b1bdc8b75125
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Citations in the corpus
- Targeted protein degradation: mechanisms, strategies and application (2022, methodology): “As the E3 ligase is responsible for recognizing substrates and its family number greatly exceeds E1 and E2, the UPS-based TPD strategies utilize E3 ligases as targeting proteins for degradation.(42) PROTAC and molecular glue are two major technologies that rely on the UPS for the degradation of prot”
- Targeting p53 pathways: mechanisms, structures and advances in therapy (2023, background): “In addition, the C-terminus of MDM2 has the enzymatic activity of E3 ubiquitin ligase, which promotes the nuclear export and degradation of p53.(335,336) MDMX (or MDM4), a homolog of MDM2, is structurally similar to MDM2, but it lacks ubiquitin ligase activity and can enhance the ubiquitination acti”