The Role of E3, E4 Ubiquitin Ligase (UBE4B) in Human Pathologies

Antoniou, N. G.; Lаgopati, Nefeli; Balourdas, Dimitrios-Ilias; Nikolaou, Michail; Papalampros, Alexandros; Vasileiou, Panagiotis; Myrianthopoulos, Vassilios; Kotsinas, Athanassios; Shiloh, Yosef; Liontos, Michalis; Gorgoulis, Vassilis G.

doi:10.3390/cancers12010062

Cited by 21 publications

(20 citation statements)

References 95 publications

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“…Previous studies have shown that the U-box catalytic domain of UBE4B is closely related to the RING-finger domain of MDM2 and is responsible for its E3 activity, and these two enzymes are considered significant regulators of P53 through the ubiquitination process [ 17 , 31 – 33 ]. UBE4A , as a homolog of UBE4B [ 17 ], may also exert the same effect on P53 . To verify this claim, we performed qRT-PCR and WB analysis in UBE4A knockdown CRC cell lines and their corresponding negative control cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have implicated UBE4B as a regulator of P53 [ 15 – 18 ]; the U box catalytic domain is closely related to the RING-finger domain of MDM2 and is responsible for its E3 activity. These two enzymes are considered significant regulators of P53 through the ubiquitination process [ 17 ]. However, the function of UBE4A , as a U box catalytic domain-containing E3 ubiquitin ligase, remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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PTBP3 modulates P53 expression and promotes colorectal cancer cell proliferation by maintaining UBE4A mRNA stability

Xie

Long

et al. 2022

Cell Death Dis

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The RNA binding protein PTBP3 was recently reported to play a critical role in multiple cancers, and the molecular mechanisms involved RNA splicing, 3′ end processing and translation. However, the role of PTBP3 in colorectal cancer (CRC) remains poorly explored. Herein, PTBP3 was upregulated in CRC and associated with a poor prognosis. PTBP3 knockdown in colorectal cancer cell lines restricted CRC proliferative capacities in vitro and in vivo. Mechanistically, PTBP3 regulated the expression of the E3 ubiquitin ligase UBE4A by binding the 3′ UTR of its mRNA, preventing its degradation. UBE4A participated in P53 degradation, and PTBP3 knockdown in colorectal cancer cell lines showed increased P53 expression. UBE4A overexpression rescued PTBP3 knockdown-induced inhibition of CRC cell proliferation and P53 expression. Our results demonstrated that PTBP3 plays an essential role in CRC cell proliferation by stabilizing UBE4A to regulate P53 expression and may serve as a new prognostic biomarker and effective therapeutic target for CRC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PTBP3 modulates P53 expression and promotes colorectal cancer cell proliferation by maintaining UBE4A mRNA stability

Xie

Long

et al. 2022

Cell Death Dis

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“…There are an estimated 600-700 E3 ligase genes representing approximately 5% of the human genome [36]. Ubiquitin ligases can promote the degradation of either oncogenes or tumorsuppressor genes, thus E3s are themselves "druggable" enzymes or serve as potential cancer targets [37,38]. The E3 ubiquitin-ligase enzyme is important for the specific binding of ubiquitin to its target substrate, which depends on their specific domains [39].…”

Section: Ubiquitination and Deubiquitinationmentioning

confidence: 99%

The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer

Puranik

Bui

Yadav

et al. 2021

IJMS

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The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system.

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“…E4 ubiquitin ligases play roles in highly processive chain elongation but not in the initial steps of ubiquitination [ 79 , 80 , 81 , 82 , 83 ]. E4 ligases not only play complementary roles to E3 ligases but also facilitate the function of E3 ligases under certain circumstances, which extends the length of polyubiquitin chains [ 80 , 84 ].…”

Section: Ubiquitinationmentioning

confidence: 99%

How Is the Fidelity of Proteins Ensured in Terms of Both Quality and Quantity at the Endoplasmic Reticulum? Mechanistic Insights into E3 Ubiquitin Ligases

Kang

Jeon

2021

IJMS

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The endoplasmic reticulum (ER) is an interconnected organelle that plays fundamental roles in the biosynthesis, folding, stabilization, maturation, and trafficking of secretory and transmembrane proteins. It is the largest organelle and critically modulates nearly all aspects of life. Therefore, in the endoplasmic reticulum, an enormous investment of resources, including chaperones and protein folding facilitators, is dedicated to adequate protein maturation and delivery to final destinations. Unfortunately, the folding and assembly of proteins can be quite error-prone, which leads to the generation of misfolded proteins. Notably, protein homeostasis, referred to as proteostasis, is constantly exposed to danger by flows of misfolded proteins and subsequent protein aggregates. To maintain proteostasis, the ER triages and eliminates terminally misfolded proteins by delivering substrates to the ubiquitin–proteasome system (UPS) or to the lysosome, which is termed ER-associated degradation (ERAD) or ER-phagy, respectively. ERAD not only eliminates misfolded or unassembled proteins via protein quality control but also fine-tunes correctly folded proteins via protein quantity control. Intriguingly, the diversity and distinctive nature of E3 ubiquitin ligases determine efficiency, complexity, and specificity of ubiquitination during ERAD. ER-phagy utilizes the core autophagy machinery and eliminates ERAD-resistant misfolded proteins. Here, we conceptually outline not only ubiquitination machinery but also catalytic mechanisms of E3 ubiquitin ligases. Further, we discuss the mechanistic insights into E3 ubiquitin ligases involved in the two guardian pathways in the ER, ERAD and ER-phagy. Finally, we provide the molecular mechanisms by which ERAD and ER-phagy conduct not only protein quality control but also protein quantity control to ensure proteostasis and subsequent organismal homeostasis.

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The Role of E3, E4 Ubiquitin Ligase (UBE4B) in Human Pathologies

Cited by 21 publications

References 95 publications

PTBP3 modulates P53 expression and promotes colorectal cancer cell proliferation by maintaining UBE4A mRNA stability

PTBP3 modulates P53 expression and promotes colorectal cancer cell proliferation by maintaining UBE4A mRNA stability

The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer

How Is the Fidelity of Proteins Ensured in Terms of Both Quality and Quantity at the Endoplasmic Reticulum? Mechanistic Insights into E3 Ubiquitin Ligases

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