Minocycline accelerates hypoxia-inducible factor-1 alpha degradation and inhibits hypoxia-induced neovasculogenesis through prolyl hydroxylase, von Hippel–Lindau-dependent pathway

2013 ◽  
Author(s):  
Ching-Hao Li ◽  
Po-Lin Liao ◽  
Ya-Ting Yang ◽  
Shih-Hsuan Huang ◽  
Cheng-Hui Lin ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Dependent Pathway

scholarly journals Enhancement of Angiogenesis Through Stabilization of Hypoxia-inducible Factor-1 by Silencing Prolyl Hydroxylase Domain-2 Gene

2008 ◽  
Vol 16 (7) ◽  
pp. 1227-1234 ◽  
Author(s):  
Shourong Wu ◽  
Nobuhiro Nishiyama ◽  
Mitsunobu R Kano ◽  
Yasuyuki Morishita ◽  
Kohei Miyazono ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Hypoxia Inducible Factor 1 ◽  
Prolyl Hydroxylase Domain

Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis

Blood ◽  
2009 ◽  
Vol 114 (10) ◽  
pp. 2015-2019 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Blood Cells ◽  
Tissue Oxygenation ◽  
Hypoxia Inducible Factor ◽  
Α Subunit ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Genes Encoding ◽  
Asparaginyl Hydroxylase

Abstract Red blood cells deliver O2 from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O2-regulated α subunit and a constitutively expressed β subunit. Hydroxylation of HIF-1α or HIF-2α by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1α or HIF-2α by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2α have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.

scholarly journals Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1α Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP

2002 ◽  
Vol 22 (9) ◽  
pp. 2984-2992 ◽  
Author(s):  
Nianli Sang ◽  
Jie Fang ◽  
Vickram Srinivas ◽  
Irene Leshchinsky ◽  
Jaime Caro
Keyword(s):  
Hypoxia Inducible Factor ◽  
Adaptation To Hypoxia ◽  
Physical Interaction ◽  
Prolyl Hydroxylases ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Transactivation Activity ◽  
Oxygen Homeostasis ◽  
Stimulation Of

ABSTRACT Hypoxia-inducible factor 1 complex (HIF-1) plays a pivotal role in oxygen homeostasis and adaptation to hypoxia. Its function is controlled by both the protein stability and the transactivation activity of its alpha subunit, HIF-1α. Hydroxylation of at least two prolyl residues in the oxygen-dependent degradation domain of HIF-1α regulates its interaction with the von Hippel-Lindau protein (VHL) that targets HIF-1α for ubiquitination and proteasomal degradation. Several prolyl hydroxylases have been found to specifically hydroxylate HIF-1α. In this report, we investigated possible roles of VHL and hydroxylases in the regulation of the transactivation activity of the C-terminal activating domain (CAD) of HIF-1α. We demonstrate that regulation of the transactivation activity of HIF-1α CAD also involves hydroxylase activity but does not require functional VHL. In addition, stimulation of the CAD activity by a hydoxylase inhibitor, hypoxia, and desferrioxamine was severely blocked by the adenoviral oncoprotein E1A but not by an E1A mutant defective in targeting p300/CBP. We further demonstrate that a hydroxylase inhibitor, hypoxia, and desferrioxamine promote the functional and physical interaction between HIF-1α CAD and p300/CBP in vivo. Taken together, our data provide evidence that hypoxia-regulated stabilization and transcriptional stimulation of HIF-1α function are regulated through partially overlapping but distinguishable pathways.

scholarly journals Nitric Oxide Modulates Oxygen Sensing by Hypoxia-inducible Factor 1-dependent Induction of Prolyl Hydroxylase 2

2006 ◽  
Vol 282 (3) ◽  
pp. 1788-1796 ◽  
Author(s):  
Utta Berchner-Pfannschmidt ◽  
Hatice Yamac ◽  
Buena Trinidad ◽  
Joachim Fandrey
Keyword(s):  
Nitric Oxide ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Hypoxia Inducible Factor 1

Expression of Hypoxia Inducible Factor 1 ?? and Von Hippel Lindau Protein in Human Middle Ear Cholesteatoma

2003 ◽  
Vol 113 (7) ◽  
pp. 1210-1215 ◽  
Author(s):  
Oliver Adunka ◽  
Wolfgang Gstoettner ◽  
Rainald Knecht ◽  
Antonius C. Kierner
Keyword(s):  
Middle Ear ◽  
Hypoxia Inducible Factor ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Middle Ear Cholesteatoma ◽  
Human Middle Ear

scholarly journals Calpain Mediates a von Hippel-Lindau Protein–independent Destruction of Hypoxia-inducible Factor-1α

2006 ◽  
Vol 17 (4) ◽  
pp. 1549-1558 ◽  
Author(s):  
Jie Zhou ◽  
Roman Köhl ◽  
Barbara Herr ◽  
Ronald Frank ◽  
Bernhard Brüne
Keyword(s):  
Renal Carcinoma ◽  
Hypoxia Inducible Factor ◽  
Active Role ◽  
Carcinoma Cells ◽  
No Donor ◽  
Human Embryonic Kidney Cells ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Calpain Inhibitors

Hypoxia-inducible factor 1 (HIF-1) is controlled through stability regulation of its alpha subunit, which is expressed under hypoxia but degraded under normoxia. Degradation of HIF-1α requires association of the von Hippel Lindau protein (pVHL) to provoke ubiquitination followed by proteasomal digestion. Besides hypoxia, nitric oxide (NO) stabilizes HIF-1α under normoxia but destabilizes the protein under hypoxia. To understand the role of NO under hypoxia we made use of pVHL-deficient renal carcinoma cells (RCC4) that show a high steady state HIF-1α expression under normoxia. Exposing RCC4 cells to hypoxia in combination with the NO donor DETA-NO (2,2′-(hydroxynitrosohydrazono) bis-ethanimine), but not hypoxia or DETA-NO alone, decreased HIF-1α protein and attenuated HIF-1 transactivation. Mechanistically, we noticed a role of calpain because calpain inhibitors reversed HIF-1α degradation. Furthermore, chelating intracellular calcium attenuated HIF-1α destruction by hypoxia/DETA-NO, whereas a calcium increase was sufficient to lower the amount of HIF-1α even under normoxia. An active role of calpain in lowering HIF-1α amount was also evident in pVHL-containing human embryonic kidney cells when the calcium pump inhibitor thapsigargin reduced HIF-1α that was stabilized by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We conclude that calcium contributes to HIF-1α destruction involving the calpain system.

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