Roles of Cullin-RING Ubiquitin Ligases in Cardiovascular Diseases

Diaz, Stephanie; Wang, Kankan; Sjögren, Benita; Liu, Xing

doi:10.3390/biom12030416

Cited by 15 publications

(8 citation statements)

References 231 publications

(248 reference statements)

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“…This induction of NRF2 is important for protection of cardiomyocytes and endothelial cells during oxidative stress. 47 However, mice with deletion of NRF2 specifically in the rostral ventrolateral medulla region of the brain stem display hypertension and impaired baroreflex function even in the absence of oxidative stress. 51 While CUL3 mutations that impair CUL3-KEAP1-mediated NRF2 ubiquitination might be expected to increase rather than decrease NRF2 abundance and activity, as demonstrated in vitro 26 and in vivo 52 for CUL3-∆9, higher NRF2 abundance could potentially raise blood pressure through central effects.…”

Section: Additional Cardiovascular Effects Of Fhht-causing Cul3 Mutat...mentioning

confidence: 99%

“…The observations that both CUL3-∆9 and CUL3 Δ474-477 may trap many substrate adaptors further raises the possibility of additional cardiovascular defects in patients with FHHt. 23,25 Many studies have pointed to roles for CRLs broadly in cardiovascular physiology (see Diaz et al 47 for a recent detailed review), but several are particularly relevant to CRL3s. Cardiomyocyte-specific disruption of Cul3 in mice is perinatal lethal, with widespread vacuolization and sarcomeric disorganization.…”

Section: Additional Cardiovascular Effects Of Fhht-causing Cul3 Mutat...mentioning

confidence: 99%

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Cullin 3 and Blood Pressure Regulation: Insights From Familial Hyperkalemic Hypertension

2023

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The study of rare monogenic forms of hypertension has led to the elucidation of important physiological pathways controlling blood pressure. Mutations in several genes cause familial hyperkalemic hypertension (also known as Gordon syndrome or pseudohypoaldosteronism type II). The most severe form of familial hyperkalemic hypertension is caused by mutations in CUL3 , encoding CUL3 (Cullin 3)—a scaffold protein in an E3 ubiquitin ligase complex that tags substrates for proteasomal degradation. In the kidney, CUL3 mutations cause accumulation of the substrate WNK (with-no-lysine [K]) kinase and ultimately hyperactivation of the renal NaCl cotransporter—the target of the first-line antihypertensive thiazide diuretics. The precise mechanisms by which mutant CUL3 causes WNK kinase accumulation have been unclear, but several functional defects are likely to contribute. The hypertension seen in familial hyperkalemic hypertension also results from effects exerted by mutant CUL3 on several pathways in vascular smooth muscle and endothelium that modulate vascular tone. This review summarizes the mechanisms by which WT (wild type) and mutant CUL3 modulate blood pressure through effects on the kidney and vasculature, potential effects in the central nervous system and heart, and future directions for investigation.

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Section: Additional Cardiovascular Effects Of Fhht-causing Cul3 Mutat...mentioning

confidence: 99%

Section: Additional Cardiovascular Effects Of Fhht-causing Cul3 Mutat...mentioning

confidence: 99%

Cullin 3 and Blood Pressure Regulation: Insights From Familial Hyperkalemic Hypertension

2023

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“…Cullins ( cul1 , 2 , 3 , 4A , 4B , 5, 7, and 9 ) constitute a distinct E3 ubiquitin ligase family by binding to ROC1/RBX1, a small RING finger protein [1]. Relative to other family members, Cul9, also named the p53-associated, PARkin-like cytoplasmic protein (PARC), shares extensive sequence homology with Cul7 [2].…”

Section: Introductionmentioning

confidence: 99%

Yes1-mediated Cul9 phosphorylation promotes the metabolic reprogramming in gastric cancer

Wu,

Zhang,

Zhang

et al. 2023

Preprint

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Although Cul9 has been implicated in human carcinogenesis, its upstream regulators and roles remain unknown. Herein, we indicate that the Cul9 promoter is hypermethylated in GCs. Bioinformatics, mass spectrometry, and unbiased-kinase screen identify the tyrosine kinase Yes1 as a key regulator of Cul9. Yes1 phosphorylates Cul9 at Y1505, promoting its selective autophagy. Patient-associated mutation of Yes1 or helicobacter pylori infection induces Cul9-Y1505 phosphorylation which switches Cul9 from a tumor-suppressor to an oncogene, as evidenced by the fact that Cul9-Y1505D knockin mice are more susceptible to gastric tumorigenesis than wild-type counterparts. Metabolic profiling and ATAC sequencing reveal that Cul9-Y1505D mutant promotes pyrimidine and purine synthesis pathways in GC. DNA-demethylating drug decitabine or HG78 compound upregulates Cul9 expression and limits GC cell proliferation in a Yes1-dependent manner. The Yes1 inhibitor CH6953755 or Leflunomide and Mycophenolate mofetil (MMF) also impair the malignancy of GC with Cul9 dysregulation. Cul9 in turn binds Yes1 and disrupts Yes1 stability, establishing a feedback circuit. Collectively, our project reveals an unrecognized role of the Yes1-Cul9 loop in GC, suggesting potential therapeutic targets.

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“…CAND1 binds to unneddylated cullins [ 1 , 2 , 3 ] and regulates cullin–RING ubiquitin ligases [ 4 , 5 , 6 ]. These ligases play a role in the ubiquitinoylation of proteins that are degraded by the proteasome system and control the stability of substrates involved in transcription and cell cycle [ 1 , 7 , 8 , 9 ]. In cancer, these ligases are frequently dysregulated [ 7 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics Analysis of the Prognostic Significance of CAND1 in ERα-Positive Breast Cancer

Alhammad

2022

Diagnostics

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The identification of novel prognostic biomarkers for breast cancer is an unmet clinical need. Cullin-associated and neddylation-dissociated 1 (CAND1) has been implicated in mediating carcinogenesis in prostate and lung cancers. In addition, CAND1 is an established prognostic biomarker for worse prognosis in liver cancer. However, the prognostic significance of CAND1 in breast cancer has not yet been explored. In this study, Breast Cancer Gene-Expression Miner (Bc-GenExMiner) and TIMER2.0 were utilized to explore the mRNA expression of CAND1 in ERα-positive breast cancer patients. The Kaplan–Meier plotter was used to explore the relationship between CAND1 expression and several prognostic indicators. The Gene Set Cancer Analysis (GSCA) web server was then used to explore the pathways of the genes that correlate with CAND1 in ERα-positive breast cancer. Immune infiltration was investigated using Bc-GenExMiner. Our bioinformatics analysis illustrates that breast cancer patients have higher CAND1 compared to normal breast tissue and that ERα-positive breast cancer patients with a high expression of CAND1 have poor overall survival (OS), distant metastasis-free survival (DMFS), and relapse-free survival (RFS) outcomes. Higher CAND1 expression was observed in histologic grade 3 compared to grades 2 and 1. Our results revealed that CAND1 positively correlates with lymph nodes and negatively correlates with the infiltration of immune cells, which is in agreement with published reports. Our findings suggest that CAND1 might mediate invasion and metastasis in ERα-positive breast cancer, possibly through the activation of estrogen and androgen signaling pathways; however, experiments should be carried out to further explore the role of CAND1 in activating the androgen and estrogen signaling pathways. In conclusion, the results suggest that CAND1 could be used as a potential novel biomarker for worse prognosis in ERα-positive breast cancer.

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Roles of Cullin-RING Ubiquitin Ligases in Cardiovascular Diseases

Cited by 15 publications

References 231 publications

Cullin 3 and Blood Pressure Regulation: Insights From Familial Hyperkalemic Hypertension

Cullin 3 and Blood Pressure Regulation: Insights From Familial Hyperkalemic Hypertension

Yes1-mediated Cul9 phosphorylation promotes the metabolic reprogramming in gastric cancer

Bioinformatics Analysis of the Prognostic Significance of CAND1 in ERα-Positive Breast Cancer

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