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

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.

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 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

E3 ubiquitin ligase TRIM7 negatively regulates NF-kappa B signaling pathway by degrading p65 in lung cancer

2020 ◽  
Vol 69 ◽  
pp. 109543 ◽  
Author(s):  
Jiangbo Jin ◽  
Zhuo Lu ◽  
Xiaomei Wang ◽  
Yufeng Liu ◽  
Tianyu Han ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathway ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Nf Kappa B

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.

scholarly journals p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Shasha Tao ◽  
Pengfei Liu ◽  
Gang Luo ◽  
Montserrat Rojo de la Vega ◽  
Heping Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Complexes ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Client Proteins

ABSTRACT Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX-containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.

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