Differential Degradation of TRA2A and PYCR2 Mediated by Ubiquitin E3 Ligase E4B

Lu, Yao; Jiang, Bo; Peng, Kangli; Li, Shasha; Liu, Xiangnan; Wang, Bufan; Chen, Yuntian; Wang, Tiepeng; Zhao, Bo

doi:10.3389/fcell.2022.833396

Cited by 3 publications

(4 citation statements)

References 42 publications

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“…Thus, proteasome inhibitors could be exploited for therapeutic use to control SR protein expression and inhibit T-ALL growth. Similar ubiquitylation-mediated control of protein degradation has been found for SRSF3, SRSF6, and TRA2A [ 115 – 117 ]. Furthermore, TRA2A is transcriptionally induced by hypoxia-inducible factor 1 subunit alpha (HIF1α) in pancreatic cancer [ 118 ].…”

Section: Designing Drugs To Target Sr–rna Interactions For Clinical Usesupporting

confidence: 66%

SR proteins in cancer: function, regulation, and small inhibitor

Bei,

2024

Cell Mol Biol Lett

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Alternative splicing of pre-mRNAs is a fundamental step in RNA processing required for gene expression in most metazoans. Serine and arginine-rich proteins (SR proteins) comprise a family of multifunctional proteins that contain an RNA recognition motif (RRM) and the ultra-conserved arginine/serine-rich (RS) domain, and play an important role in precise alternative splicing. Increasing research supports SR proteins as also functioning in other RNA-processing-related mechanisms, such as polyadenylation, degradation, and translation. In addition, SR proteins interact with N6-methyladenosine (m6A) regulators to modulate the methylation of ncRNA and mRNA. Dysregulation of SR proteins causes the disruption of cell differentiation and contributes to cancer progression. Here, we review the distinct biological characteristics of SR proteins and their known functional mechanisms during carcinogenesis. We also summarize the current inhibitors that directly target SR proteins and could ultimately turn SR proteins into actionable therapeutic targets in cancer therapy.

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Section: Designing Drugs To Target Sr–rna Interactions For Clinical Usesupporting

confidence: 66%

SR proteins in cancer: function, regulation, and small inhibitor

Bei,

2024

Cell Mol Biol Lett

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“…To investigate this, we selected five substrates: BAG2, DNAJA1, PYCR2, UNG2, and PRMT1. We have identified PYCR2 as a bona fide substrate of E4B [30], and PRMT1 is a verified substrate of both CHIP and E4B [28], while BAG2, DNAJA1 and UNG2 were identified for the first time in this study.…”

Section: Resultsmentioning

confidence: 99%

“…Although several substrates were shared by both E3s, the majority of substrate for each E3 is different. To investigate whether the U‐box domain affected substrate selectivity, PRMT1, a shared substrate of CHIP and E4B [28], and PYCR2, a E4B substrate verified in our previous study [30], were selected for this study. One putative substrate of E4B: UNG2, and two putative substrates of CHIP: BAG2 and DNAJA1, were identified for the first time.…”

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confidence: 99%

Recruitment of ubiquitin E2 enzymes is determined jointly by the U‐box domains and substrates of E3 ligases

Jin,

Li,

et al. 2024

FEBS Letters

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Ubiquitination is a cascade reaction involving E1, E2, and E3 enzymes. The orthogonal ubiquitin transfer (OUT) method has been previously established to identify potential substrates of E3 ligases. In this study, we verified the ubiquitination of five substrates mediated by the E3 ligases CHIP and E4B. To further explore the activity of U‐box domains of E3 ligases, two mutants with the U‐box domains interchanged between CHIP and E4B were generated. They exhibited a significantly reduced ubiquitination ability. Additionally, different E3s recruited similar E2 ubiquitin‐conjugating enzymes when ubiquitinating the same substrates, highlighting that U‐box domains determined the E2 recruitment, while the substrate determined the E2 selectivity. This study reveals the influence of substrates and U‐box domains on E2 recruitment, providing a novel perspective on the function of U‐box domains of E3 ligases.

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“…Additionally, by binding to the TRA2A promoter, HIF1α can upregulate the transcription of TRA2A, causing pancreatic cancer progression [17]. According to a previous study, TRA2A was significantly upregulated in HCC [18]. However, it remains unclear whether TRA2A critically affects hepatocarcinogenesis and LR.…”

Section: Ivyspring International Publishermentioning

confidence: 99%

Lnc-ZEB2-19 Inhibits the Progression and Lenvatinib Resistance of Hepatocellular Carcinoma by Attenuating the NF-κB Signaling Pathway through the TRA2A/RSPH14 Axis

Cao¹,

Ren²,

Li³

et al. 2023

Int. J. Biol. Sci.

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Long non-coding RNAs have been reported to play a crucial role in tumor progression in hepatocellular carcinoma (HCC). Lnc-ZEB2-19 has been validated to be deficiently expressed in HCC. However, the capabilities and underlying mechanisms of lnc-ZEB2-19 remain uncertain. In this study, we verified that the downregulation of lnc-ZEB2-19 was prevalent in HCC and significantly correlated with the unfavorable prognosis. Further in vitro and in vivo verified that lnc-ZEB2-19 notably inhibited the proliferation, metastasis, stemness, and lenvatinib resistance (LR) of HCC cells. Mechanistically, lnc-ZEB2-19 inhibited HCC progression and LR by specifically binding to transformer 2α (TRA2A) and promoting its degradation, which resulted in the instability of RSPH14 mRNA, leading to the downregulation of Rela(p65) and p-Rela(p-p65). Furthermore, rescue assays showed that silencing RSPH14 partially restrained the effect of knockdown expression of lnc-ZEB2-19 on HCC cell metastatic ability and stemness. The findings describe a novel regulatory axis, lnc-ZEB2-19/TRA2A/RSPH14, downregulating the nuclear factor kappa B to inhibit HCC progression and LR.

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Differential Degradation of TRA2A and PYCR2 Mediated by Ubiquitin E3 Ligase E4B

Cited by 3 publications

References 42 publications

SR proteins in cancer: function, regulation, and small inhibitor

SR proteins in cancer: function, regulation, and small inhibitor

Recruitment of ubiquitin E2 enzymes is determined jointly by the U‐box domains and substrates of E3 ligases

Lnc-ZEB2-19 Inhibits the Progression and Lenvatinib Resistance of Hepatocellular Carcinoma by Attenuating the NF-κB Signaling Pathway through the TRA2A/RSPH14 Axis

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