Impressionist portraits of mitotic exit: APC/C, K11-linked ubiquitin chains and Cezanne

Bonacci, Thomas; Emanuele, Michael J.

doi:10.1080/15384101.2019.1593646

Cited by 20 publications

(10 citation statements)

References 48 publications

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“…S6 E). To our knowledge, UBE2S, as a member of the ubiquitin-conjugating E2 enzyme, has been reported to bind to its cofactor CDC20 and mediate K11-linked ubiquitin chains on substrates 37 . To evaluate whether p16 was regulated by UBE2S, we silenced UBE2S in PCa cells with 2 different siRNAs (Fig.…”

Section: Resultsmentioning

confidence: 99%

UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer

Peng¹,

Chen²,

Huang³

et al. 2022

Int. J. Biol. Sci.

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Bone metastasis is the main site of metastasis and causes the most deaths in patients with prostate cancer (PCa). The mechanism of bone metastasis is complex and not fully clarified. By RNA sequencing and analysing key pathways in bone metastases of PCa, we found that one of the most important characteristics during PCa bone metastasis was G1/S transition acceleration caused by low protein levels of p16INK4a (p16). Interestingly, we demonstrated that UBE2S bound and degraded p16 through K11- rather than K48- or K63-linked ubiquitination, which accelerated PCa tumour cell G1/S transition in vivo and in vitro . Moreover, UBE2S also stabilized β-catenin through K11-linked ubiquitination, leading to enhanced migration and invasion of tumour cells in PCa bone metastasis. Based on our cohorts and public databases, UBE2S was overexpressed in bone metastases and positively correlated with a high Gleason score, advanced nodal metastasis status and poor prognosis in PCa. Finally, targeting UBE2S with cephalomannine inhibited proliferation and invasion in vitro , and bone metastasis of PCa in vivo . This study innovatively discovered that UBE2S plays an oncogenic role in bone metastasis of PCa by degrading p16 and stabilizing β-catenin via K11-linked ubiquitination, suggesting that it may serve as a multipotent target for metastatic PCa treatment.

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Section: Resultsmentioning

confidence: 99%

UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer

Peng¹,

Chen²,

Huang³

et al. 2022

Int. J. Biol. Sci.

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“…112,113 CYLD is more likely to act on linear ubiquitination and the K63 linkage Ub chain. 114 Similarly, OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) specifically acts on K48-linked ubiquitination, 115,116 with Cezanne specifically removing the K11 linkage Ub chain, 117,118 and TRABID specifically recognizing the K29-linked or K33-linked Ub chain. 119 These specific Ub-type deubiquitinating enzymes cannot remove the last molecule of Ub-modified on the substrate, which may generate a monoubiquitinated substrate protein.…”

Section: Deubiquitinating Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

464

308

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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.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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“…K48 ubiquitylation correlates the recruitment of proteasomal subunits 10 . Like K48, LLPUC of K11 conjugated substrates are also targeted to proteasomal degradation 21,28,29 . In fact, the so-called "non-canonical" K11 linkage is as abundant as the "canonical" K48 linkages in cells 13,30 .…”

Section: Discussionmentioning

confidence: 99%

“…R23a, with C-terminal ubiquitinassociated (UBA) domain, preferentially binds K48-linked chains of substrates and transfer substrates to the proteasome 42 . S5a and Adrm1 on the 26S proteasome prefer to recognize K48 and K11 linkage ubiquitinylated substrates for degradation 21,28 . Our data were similar to those in a most recently published report that S5a preferably selects K48-or K11-linked substrates 21 .…”

Section: Discussionmentioning

confidence: 99%

Opposite Regulation of F508del-CFTR Biogenesis by Four Poly-Lysine Ubiquitin Chains

Henri

Yao

et al. 2020

Preprint

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Background: As a misfolding protein, more than 99% of F508del-CFTR (F508del) is degraded by the ubiquitin-proteasome system before its maturation, which results in almost no membrane expression of CFTR and thereby no chloride secretion across epithelial cells of cystic fibrosis patients. The conjugation of ubiquitin chains to the protein substrates is necessary for ubiquitin-mediated proteasomal degradation. Ubiquitin contains seven lysine (K) residues (K6, K11, K27, K29, K33, K48, and K63), all of them can be conjugated one to another forming poly-ubiquitin chains on substrates by mixing together or by only one type of lysine that provides sorting signals for different pathways. Results: Here we report that four lysine linked poly-Ub chains (LLPUCs) were involved in F508del biogenesis: two LLPUCs linked by K11 or K48 of Ub facilitated F508del degradation; whereas the other two linked by K63 and K33 of Ub protected F508del from degradation. LLPUC K11 is more potent for F508del degradation than K48. Moreover, E3 ligase CHIP and RNF5 catalyzed LLPUCs K48 formation and RNF5 also catalyzed LLPUC K11 formation on F508del. Importantly, Those LLPUCs provide F508del with different affinities to the proteasomal shuttle protein (Rad23a) and the proteasomal receptors (Adrm1 and S5a), offering a mechanistic insight of differential regulation F508del different by different LLPUCs. Conclusions: F508del utilizes four specific lysine-linked poly Ub chains and during its biogenesis for opposite destiny through different identification by proteasomal shuttle protein or receptors. These findings provide new insights to understand the CF pathogenesis and are expected to facilitate the development of therapies for this devastating disease.

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Impressionist portraits of mitotic exit: APC/C, K11-linked ubiquitin chains and Cezanne

Cited by 20 publications

References 48 publications

UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer

UBE2S as a novel ubiquitinated regulator of p16 and β-catenin to promote bone metastasis of prostate cancer

The role of ubiquitination in tumorigenesis and targeted drug discovery

Opposite Regulation of F508del-CFTR Biogenesis by Four Poly-Lysine Ubiquitin Chains

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