Abstract
AG490 is a tyrphostin originally described as a Janus Activated Kinase (JAK) 2 inhibitor. AG490 also inhibits epidermal growth factor receptor (EGFR) and guanylyl cyclases (GC). More recently, AG490 was associated with oxidative stress protection in experimental acute kidney injury models. We now show that AG490 is also a strong activator of the Hypoxia Inducible Factor (HIF)-1. Under normoxic conditions HIF-1α is degraded through hydroxylation, von Hippel Lindau protein (VHL)-mediated ubiquitin tagging and proteasomal degradation. AG490 increased HIF-1α protein, but not HIF-1α mRNA levels, dose- and time-dependently in cultured endothelial, vascular smooth muscle and kidney proximal tubular epithelial cells. AG490 increased HIF-1α protein half-life, suggesting that HIF-1α protein accumulation resulted from a decreased degradation. In this regard, AG490 prevented HIF-1α hydroxylation and increased HIF-1α protein levels in human renal carcinoma cells expressing VHL, but did not further increase HIF-1α in VHL negative cells. AG490 did not prevent the proteasomal degradation of other proteins. HIF-1α was not upregulated by dominant negative JAK2constructs, tyrphostin AG9, the EGFR inhibitors erbstatin and genistein, the GC inhibitor Ly83583 or cGMP analogues. Finally, AG490 also increased HIF-1α transcriptional activity evidenced by the increased HIF-1α-dependent VEGF expression. In conclusion, AG490 is a novel HIF-1α activator that increases HIF-1α half-life and protein levels through interference with HIF-1α hydroxylation and VHL-mediated degradation. This action may contribute to the cell and tissue protective effects of AG490.
Keywords: Acute kidney injury, endothelium, HIF-1α, hypoxia, JAK2, kidney cancer, tyrphostin, tubular cell, vascular smooth muscle, VEGF, VHL
Current Medicinal Chemistry
Title:AG490 Promotes HIF-1α Accumulation by Inhibiting Its Hydroxylation
Volume: 19 Issue: 23
Author(s): R. Fernandez-Sanchez, S. Berzal, Maria-Dolores Sanchez-Nino, F. Neria, S. Goncalves, O. Calabia, A. Tejedor, M. J. Calzada, C. Caramelo, J. J.P. Deudero and A. Ortiz
Affiliation:
Keywords: Acute kidney injury, endothelium, HIF-1α, hypoxia, JAK2, kidney cancer, tyrphostin, tubular cell, vascular smooth muscle, VEGF, VHL
Abstract: AG490 is a tyrphostin originally described as a Janus Activated Kinase (JAK) 2 inhibitor. AG490 also inhibits epidermal growth factor receptor (EGFR) and guanylyl cyclases (GC). More recently, AG490 was associated with oxidative stress protection in experimental acute kidney injury models. We now show that AG490 is also a strong activator of the Hypoxia Inducible Factor (HIF)-1. Under normoxic conditions HIF-1α is degraded through hydroxylation, von Hippel Lindau protein (VHL)-mediated ubiquitin tagging and proteasomal degradation. AG490 increased HIF-1α protein, but not HIF-1α mRNA levels, dose- and time-dependently in cultured endothelial, vascular smooth muscle and kidney proximal tubular epithelial cells. AG490 increased HIF-1α protein half-life, suggesting that HIF-1α protein accumulation resulted from a decreased degradation. In this regard, AG490 prevented HIF-1α hydroxylation and increased HIF-1α protein levels in human renal carcinoma cells expressing VHL, but did not further increase HIF-1α in VHL negative cells. AG490 did not prevent the proteasomal degradation of other proteins. HIF-1α was not upregulated by dominant negative JAK2constructs, tyrphostin AG9, the EGFR inhibitors erbstatin and genistein, the GC inhibitor Ly83583 or cGMP analogues. Finally, AG490 also increased HIF-1α transcriptional activity evidenced by the increased HIF-1α-dependent VEGF expression. In conclusion, AG490 is a novel HIF-1α activator that increases HIF-1α half-life and protein levels through interference with HIF-1α hydroxylation and VHL-mediated degradation. This action may contribute to the cell and tissue protective effects of AG490.
Export Options
About this article
Cite this article as:
Fernandez-Sanchez R., Berzal S., Sanchez-Nino Maria-Dolores, Neria F., Goncalves S., Calabia O., Tejedor A., J. Calzada M., Caramelo C., J.P. Deudero J. and Ortiz A., AG490 Promotes HIF-1α Accumulation by Inhibiting Its Hydroxylation, Current Medicinal Chemistry 2012; 19 (23) . https://dx.doi.org/10.2174/092986712802002554
DOI https://dx.doi.org/10.2174/092986712802002554 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
mTOR: A Novel Therapeutic Target for Diseases of Multiple Systems
Current Drug Targets The role of NADPH Oxidase in Vascular Disease – Hypertension, Atherosclerosis & Stroke
Current Pharmaceutical Design Exercise-Induced Cardioprotection via eNOS: A Putative Role of Red Blood Cell Signaling
Current Medicinal Chemistry Role of Nitric Oxide in Liver Injury
Current Molecular Medicine Patent Selections
Recent Patents on Cardiovascular Drug Discovery Use of Naturally Occurring Peptides for Neuropathic Spinal Cord Injury Pain
Current Protein & Peptide Science Acute Coronary Syndromes as Auto-Inflammatory Disorders
Current Pharmaceutical Design Recent Progress Toward Hydrogen Medicine: Potential of Molecular Hydrogen for Preventive and Therapeutic Applications
Current Pharmaceutical Design Cardiac and Metabolic Consequences of Aerobic Exercise Training in Experimental Diabetes
Current Diabetes Reviews Clinical Uses of Melatonin in Neurological Diseases and Mental and Behavioural Disorders
Current Medicinal Chemistry Cross-Talk Between TGF-β and NADPH Oxidases During Liver Fibrosis and Hepatocarcinogenesis
Current Pharmaceutical Design Good, Bad, Mobile Elements: Genome’s Most Successful “Parasites” as Emerging Players in Cell and Organismal Aging
Current Pharmaceutical Design Pathophysiology of Coronary Thrombus Formation and Adverse Consequences of Thrombus During PCI
Current Cardiology Reviews Phosphodiesterase 5 Inhibitors in the Treatment of Erectile Dysfunction
Current Pharmaceutical Design From Anreps Phenomenon to Myocardial Hypertrophy: Role of the Na+/H+ Exchanger
Current Cardiology Reviews Ocular Application of Macrobiomolecules in Anti-Allergy and Anti- Inflammation
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Human Adipose-Derived Stem Cells Delay Retinal Degeneration in Royal College of Surgeons Rats Through Anti-Apoptotic and VEGF-Mediated Neuroprotective Effects
Current Molecular Medicine Targeting Matrix Metalloproteinases in Inflammatory Conditions
Current Drug Targets Copper and Heme-Mediated Abeta Toxicity: Redox Chemistry, Abeta Oxidations and Anti-ROS Compounds
Current Topics in Medicinal Chemistry Pharmacological Interventions and Rehabilitation Approach for Enhancing Brain Self-repair and Stroke Recovery
Current Neuropharmacology