Abstract A14: DNA alterations to the Cullin-3/Ring box protein-1 E3 ubiquitin ligase complex represent a novel mechanism of NF-κB activation in lung cancer

2010 ◽  
Author(s):  
Larissa Pikor ◽  
Kelsie L. Thu ◽  
William W. Lockwood ◽  
Raj Chari ◽  
Ian M. Wilson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligase Complex ◽  
Cullin 3 ◽  
Dna Alterations

scholarly journals Revisiting the NaCl cotransporter regulation by with-no-lysine kinases

2015 ◽  
Vol 308 (10) ◽  
pp. C779-C791 ◽  
Author(s):  
Silvana Bazúa-Valenti ◽  
Gerardo Gamba
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Type Ii ◽  
Complex Issue ◽  
Dark Ages ◽  
Ubiquitin Ligase Complex ◽  
Pseudohypoaldosteronism Type Ii ◽  
Cullin 3 ◽  
Increased Activity ◽  
Pseudohypoaldosteronism Type

The renal thiazide-sensitive Na+-Cl− cotransporter (NCC) is the salt transporter in the distal convoluted tubule. Its activity is fundamental for defining blood pressure levels. Decreased NCC activity is associated with salt-remediable arterial hypotension with hypokalemia (Gitelman disease), while increased activity results in salt-sensitive arterial hypertension with hyperkalemia (pseudohypoaldosteronism type II; PHAII). The discovery of four different genes causing PHAII revealed a complex multiprotein system that regulates the activity of NCC. Two genes encode for with-no-lysine (K) kinases WNK1 and WNK4, while two encode for kelch-like 3 (KLHL3) and cullin 3 (CUL3) proteins that form a RING type E3 ubiquitin ligase complex. Extensive research has shown that WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and that WNKs modulate the activity of NCC by means of intermediary Ste20-type kinases known as SPAK or OSR1. The understanding of the effect of WNKs on NCC is a complex issue, but recent evidence discussed in this review suggests that we could be reaching the end of the dark ages regarding this matter.

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 Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs

2022 ◽  
Author(s):  
Antonio Cuevas-Navarro ◽  
Laura Rodriguez-Muñoz ◽  
Joaquim Grego-Bessa ◽  
Alice Cheng ◽  
Katherine A Rauen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Null Allele ◽  
E3 Ubiquitin Ligase ◽  
Adaptor Protein ◽  
Loss Of Function ◽  
Ras Gtpases ◽  
Ubiquitin Ligase Complex ◽  
Species Analysis ◽  
Cullin 3 ◽  
Ring E3

RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of canonical RAS GTPases. Here, we have analyzed the phenotypes of LZTR1 loss-of-function mutants in both fruit flies and mice and have demonstrated biochemical dependency on their RIT1 orthologs. Moreover, we show that LZTR1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of RIT1.

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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