SEMINAR: Cardiodegeneration and the paradoxical response of the antioxidant response protein Nrf2
|Cardiodegeneration and the paradoxical response of the antioxidant response protein Nrf2 : School of Human Sciences (APHB) Seminar Series
Speaker: Professor Des Richardson holds the Chair of Cancer Cell Biology at the University of Sydney, Australia, and is a National Health and Medical Research Council (NHMRC) of Australia Senior Principal Research Fellow.
He has published > 407 articles, reviews, patents, chapters etc., over his career with >93% as first, senior or corresponding author (H-index: 80; >24,255 citations over entire career; with >13,750 citations over the past 5 years and H-index: 55 over past 5 years: Google Scholar Accessed 10 Jan, 2018).
He is Executive Editor of BBA-General Subjects and has served on the Editorial Boards of >40 international journals, including J. Biol. Chem., Antioxidants Redox Signaling, Biochem. J., BBA-Mol Cell Res, Mol. Pharmacol., Pharmacol. Res., etc.
As a major translational research achievement, he has developed the anti-cancer and anti-metastatic drug, DpC, which overcomes P-glycoprotein mediated drug resistance.
This has led to commercialisation of DpC and the development of the international company, Oncochel Therapeutics LLC, USA and its Australian subsidiary, Oncochel Therapeutics Pty Ltd. Notably, DpC has entered multi-centre Phase I clinical trials for the treatment of advanced and resistant cancer.
Abstract: Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the antioxidant response. However, studies in models of Friedreich ataxia, a neurodegenerative and cardiodegenerative disease associated with oxidative stress, reported decreased Nrf2 expression attributable to unknown mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues.
Frataxin KO results in fatal cardiomyopathy, whereas skeletal muscle was asymptomatic. In the KO heart, protein oxidation and a decreased glutathione/oxidized glutathione ratio were observed, but the opposite was found in skeletal muscle. Decreased total and nuclear Nrf2 and increased levels of its inhibitor, Kelch-like ECH-associated protein 1, were evident in the KO heart, but not in skeletal muscle.
Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling was demonstrated in the KO heart. This process involved the following: i) increased Gsk3β activation, ii) β-transducin repeat containing E3 ubiquitin protein ligase nuclear accumulation, and iii) Fyn phosphorylation. A corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA were observed in KO hearts. Paradoxically, protein levels of some Nrf2 antioxidant targets were significantly increased in KO mice.
Collectively, cardiac frataxin deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Kelch-like ECH-associated protein 1 and activation of Gsk3β signaling, which decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.
Professor Des Richardson, Chair of Cancer Cell Biology, NHMRC Senior Principal Research Fellow, The University of Sydney
Seminar room 1.81 (first floor) Anatomy building, The University of Western Australia
: 6488 3313
Mon, 15 Jan 2018 13:00
Mon, 15 Jan 2018 14:00
Deborah Hull <email@example.com>
Fri, 21 Sep 2018 09:29
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