scholarly journals Unique Pattern of Component Gene Disruption in the NRF2 Inhibitor KEAP1/CUL3/RBX1 E3-Ubiquitin Ligase Complex in Serous Ovarian Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Victor D. Martinez ◽  
Emily A. Vucic ◽  
Kelsie L. Thu ◽  
Larissa A. Pikor ◽  
Roland Hubaux ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Related Factor ◽  
Ovarian Carcinomas ◽  
Nrf2 Pathway ◽  
Unique Pattern ◽  
Ubiquitin Ligase Complex ◽  
Nrf2 Target Gene ◽  
Complex Components

The NFE2-related factor 2 (NRF2) pathway is critical to initiate responses to oxidative stress; however, constitutive activation occurs in different cancer types, including serous ovarian carcinomas (OVCA). The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is a regulator of NRF2 levels. Hence, we investigated the DNA-level mechanisms affecting these genes in OVCA. DNA copy-number loss (CNL), promoter hypermethylation, mRNA expression, and sequence mutation forKEAP1,CUL3, andRBX1were assessed in a cohort of 568 OVCA from The Cancer Genome Atlas. Almost 90% of cases exhibited loss-of-function alterations in any components of the NRF2 inhibitory complex. CNL is the most prominent mechanism of component disruption, with RBX1 being the most frequently disrupted component. These alterations were associated with reduced mRNA expression of complex components, and NRF2 target gene expression was positively enriched in 90% of samples harboring altered complex components. Disruption occurs through a unique DNA-level alteration pattern in OVCA. We conclude that a remarkably high frequency of DNA and mRNA alterations affects components of the KEAP1/CUL3/RBX1 complex, through a unique pattern of genetic mechanisms. Together, these results suggest a key role for the KEAP1/CUL3/RBX1 complex and NRF2 pathway deregulation in OVCA.

scholarly journals Genetic Disruption of KEAP1/CUL3 E3 Ubiquitin Ligase Complex Components is a Key Mechanism of NF-KappaB Pathway Activation in Lung Cancer

2011 ◽  
Vol 6 (9) ◽  
pp. 1521-1529 ◽  
Author(s):  
Kelsie L. Thu ◽  
Larissa A. Pikor ◽  
Raj Chari ◽  
Ian M. Wilson ◽  
Calum E. MacAulay ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Pathway Activation ◽  
Ubiquitin Ligase Complex ◽  
Nf Kappab ◽  
Complex Components

CRL2-KLHDC3 E3 ubiquitin ligase complex suppresses ferroptosis through promoting p14ARF degradation

2021 ◽  
Author(s):  
Pingzhao Zhang ◽  
Kun Gao ◽  
Liang Zhang ◽  
Huiru Sun ◽  
Xiaying Zhao ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligase Complex

scholarly journals TFEB activates Nrf2 by repressing its E3 ubiquitin ligase DCAF11 and promoting phosphorylation of p62

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jee-Yun Park ◽  
Sunhyo Kim ◽  
Hee Young Sohn ◽  
Young Ho Koh ◽  
Chulman Jo
Keyword(s):  
Oxidative Stress ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Biological Response ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Glutathione S Transferase ◽  
First Time ◽  
Cellular Stressors

Abstract Transcriptional factor EB (TFEB) and nuclear factor E2-related factor 2 (Nrf2) play crucial roles in the biological response against cellular stressors; however, their relationship has not yet been investigated. Here, we constructed human neuroglioma cell lines stably expressing TFEB. The expression of Nrf2-response genes, including heme oxygenase (HO)-1, glutathione-s-transferase-mu1 (GSTM1), and p62, was induced in the cell line, independent of oxidative stress. Of note, the protein level of Nrf2 was significantly increased, and its ubiquitinated fraction was reduced in stable cells compared to that in the control cells. Among E3 ubiquitin ligases known to be involved in the ubiquitination of Nrf2, DDB1 and Cullin4 associated factor 11 (DCAF11) was down-regulated at both protein and mRNA levels in stable cells, indicating that the repression of DCAF11 by TFEB may be mainly involved in the stabilization of Nrf2. In addition, the level of phosphorylated p62 at S349 was highly increased in stable cells compared to that in control cells, which could allow it to interfere with the association of Keap1 and Nrf2, thus stabilizing Nrf2. We suggest for the first time that TFEB could activate Nrf2 by increasing its stability under conditions devoid of oxidative stress.

scholarly journals The APC/CTE E3 Ubiquitin Ligase Complex Mediates the Antagonistic Regulation of Root Growth and Tillering by ABA and GA

2020 ◽  
Vol 32 (6) ◽  
pp. 1973-1987
Author(s):  
Qibing Lin ◽  
Zhe Zhang ◽  
Fuqing Wu ◽  
Miao Feng ◽  
Yao Sun ◽  
...  
Keyword(s):  
Root Growth ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligase Complex

Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3

2015 ◽  
Vol 43 (4) ◽  
pp. 611-620 ◽  
Author(s):  
John D. Hayes ◽  
Sudhir Chowdhry ◽  
Albena T. Dinkova-Kostova ◽  
Calum Sutherland
Keyword(s):  
Transcription Factor ◽  
Growth Factors ◽  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Proteasomal Degradation ◽  
Regulation Of Transcription ◽  
Related Factor ◽  
Nrf2 Target Gene ◽  
The Stability

Nuclear factor-erythroid 2 p45 (NF-E2 p45)-related factor 2 (Nrf2) is a master regulator of redox homoeostasis that allows cells to adapt to oxidative stress and also promotes cell proliferation. In this review, we describe the molecular mechanisms by which oxidants/electrophilic agents and growth factors increase Nrf2 activity. In the former case, oxidants/electrophiles increase the stability of Nrf2 by antagonizing the ability of Kelch-like ECH-associated protein 1 (Keap1) to target the transcription factor for proteasomal degradation via the cullin-3 (Cul3)–RING ubiquitin ligase CRLKeap1. In the latter case, we speculate that growth factors increase the stability of Nrf2 by stimulating phosphoinositide 3-kinase (PI3K)−protein kinase B (PKB)/Akt signalling, which in turn results in inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) and in doing so prevents the formation of a DSGIS motif-containing phosphodegron in Nrf2 that is recognized by the β-transducin repeat-containing protein (β-TrCP) Cul1-based E3 ubiquitin ligase complex SCFβ-TrCP. We present data showing that in the absence of Keap1, the electrophile tert-butyl hydroquinone (tBHQ) can stimulate Nrf2 activity and induce the Nrf2-target gene NAD(P)H:quinone oxidoreductase-1 (NQO1), whilst simultaneously causing inhibitory phosphorylation of GSK-3β at Ser9. Together, these observations suggest that tBHQ can suppress the ability of SCFβ-TrCP to target Nrf2 for proteasomal degradation by increasing PI3K−PKB/Akt signalling. We also propose a scheme that explains how other protein kinases that inhibit GSK-3 could stimulate induction of Nrf2-target genes by preventing formation of the DSGIS motif-containing phosphodegron in Nrf2.

scholarly journals UBE2G1 governs the destruction of cereblon neomorphic substrates

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Gang Lu ◽  
Stephanie Weng ◽  
Mary Matyskiela ◽  
Xinde Zheng ◽  
Wei Fang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Antitumor Activities ◽  
Fundamental Interest ◽  
Myeloma Cells ◽  
Ubiquitin Ligase Complex ◽  
Clinical Resistance ◽  
Conjugating Enzymes ◽  
Ubiquitin Conjugating Enzymes

The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4CRBN neomorphic substrates via a sequential ubiquitination mechanism. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, it will be of fundamental interest to explore if loss of UBE2G1 activity is linked to clinical resistance to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins.

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