Abstract
As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases.
MeSH Terms
Amino Acid Sequence
Animals
Bridged Bicyclo Compounds/pharmacology
Carrier Proteins/genetics,metabolism
Dose-Response Relationship, Drug
Embryo, Nonmammalian/drug effects,physiology
Embryonic Development
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Mitochondria/genetics,metabolism
Molecular Sequence Data
Morpholinos/pharmacology
Neovascularization, Physiologic/genetics
Prognosis
Vascular Endothelial Growth Factor A/genetics,metabolism
Zebrafish/genetics,physiology
Chemicals
Bridged Bicyclo Compounds
Carrier Proteins
Morpholinos
Vascular Endothelial Growth Factor A
ubiquinone-binding proteins
terpestacin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Cho Yoon Sun
Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Jung Hye Jin
Seok Seung Hyeok
Payumo Alexander Y
Chen James K
Kwon Ho Jeong
References (23)
23 references, click to expand
-
Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model.
Breast Cancer Res Treat. 2009 Jan;113(1):101-11
PMID: 18256928
-
Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism.
Adv Drug Deliv Rev. 2009 Nov 30;61(14):1250-75
PMID: 19716393
-
Assembly of the mitochondrial membrane system. Analysis of structural mutants of the yeast coenzyme QH2-cytochrome c reductase complex.
J Biol Chem. 1988 Oct 5;263(28):14323-33
PMID: 2844766
-
Patterning of angiogenesis in the zebrafish embryo.
Development. 2002 Feb;129(4):973-82
PMID: 11861480
-
A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure.
Nat Genet. 2001 Sep;29(1):57-60
PMID: 11528392
-
Zebrafish bioassay-guided natural product discovery: isolation of angiogenesis inhibitors from East African medicinal plants.
PLoS One. 2011 Feb 17;6(2):e14694
PMID: 21379387
-
Effective targeted gene 'knockdown' in zebrafish.
Nat Genet. 2000 Oct;26(2):216-20
PMID: 11017081
-
Polymorphisms in the mitochondrial oxidative phosphorylation chain genes as prognostic markers for colorectal cancer.
BMC Med Genet. 2012 Apr 30;13:31
PMID: 22545919
-
Platelet-derived growth factor receptor beta is critical for zebrafish intersegmental vessel formation.
PLoS One. 2010 Jun 25;5(6):e11324
PMID: 20593033
-
Automated, quantitative screening assay for antiangiogenic compounds using transgenic zebrafish.
Cancer Res. 2007 Dec 1;67(23):11386-92
PMID: 18056466
-
Arteries and veins: making a difference with zebrafish.
Nat Rev Genet. 2002 Sep;3(9):674-82
PMID: 12209142
-
Angiogenesis: how a tumor adapts to hypoxia.
Biochem Biophys Res Commun. 1999 Dec 29;266(3):718-22
PMID: 10603309
-
In vivo imaging of embryonic vascular development using transgenic zebrafish.
Dev Biol. 2002 Aug 15;248(2):307-18
PMID: 12167406
-
The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients.
Diabetes Res Clin Pract. 2008 Jul;81(1):56-60
PMID: 18358555
-
Anti-angiogenic Effects of Metformin, an AMPK Activator, on Human Umbilical Vein Endothelial Cells and on Granulation Tissue in Rat.
Iran J Basic Med Sci. 2012 Nov;15(6):1202-9
PMID: 23653852
-
Morpholino antisense oligomers: design, preparation, and properties.
Antisense Nucleic Acid Drug Dev. 1997 Jun;7(3):187-95
PMID: 9212909
-
Oligomycin inhibits HIF-1alpha expression in hypoxic tumor cells.
Am J Physiol Cell Physiol. 2005 May;288(5):C1023-9
PMID: 15840558
-
Rapid analysis of angiogenesis drugs in a live fluorescent zebrafish assay.
Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):911-2
PMID: 12740225
-
Mitochondrial respiratory-chain diseases.
N Engl J Med. 2003 Jun 26;348(26):2656-68
PMID: 12826641
-
Terpestacin inhibits tumor angiogenesis by targeting UQCRB of mitochondrial complex III and suppressing hypoxia-induced reactive oxygen species production and cellular oxygen sensing.
J Biol Chem. 2010 Apr 9;285(15):11584-95
PMID: 20145250
-
Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1.
Cardiovasc Res. 2009 Aug 1;83(3):566-74
PMID: 19414528
-
A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis.
Hum Genet. 2003 Jul;113(2):118-22
PMID: 12709789
-
Identification of tumor suppressors and oncogenes from genomic and epigenetic features in ovarian cancer.
PLoS One. 2011;6(12):e28503
PMID: 22174824