Ca2+/Calmodulin Kinase-dependent Activation of Hypoxia Inducible Factor 1 Transcriptional Activity in Cells Subjected to Intermittent Hypoxia

Yuan, Guoxiang; Nanduri, Jayasri; Bhasker, C. Raman; Semenza, Gregg L.; Prabhakar, Nanduri R.

doi:10.1074/jbc.m407706200

Cited by 215 publications

(219 citation statements)

References 47 publications

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“…They observed significant upregulation of HIF1α levels in carotid bodies of mice 99 . Similar results were seen in vitro with the PC12 cell line 100 . The mechanism of enhanced HIF1 activity is multifactorial, stemming from alteration in the rate of HIF1α synthesis, regulated by mTOR (also known as FRAP1), and phosphorylation of the HIF1 binding cofactor CBP (also known as p300 and CREBBP) 101 .…”

Section: Mechanisms Underlying Cycling Hypoxia and Implicationssupporting

confidence: 85%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Mechanisms Underlying Cycling Hypoxia and Implicationssupporting

confidence: 85%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…HIFb is constitutively expressed in cells, while, under normoxic condition, HIFa is hydroxylated by HIF prolyl-hydroxylase, The ''proline'' hydroxylated form of HIFa is recognized by von Hippel-Lindau (VHL) tumor suppressor protein as part of a complex with E3 ubiquitin ligase which makes HIFa a target for degradation by an E3 ubiquitin ligase, leading to quick degradation by proteasome [12,13]. It has been shown that hypoxia increases HIFa stability and therefore HIF activity by reactive oxygen species (ROS)-induced activation of calcium-calmodulin kinase (CamK) and protein kinase C (PKC) [14,15]. Recent studies have suggested that hypoxia-independent mechanisms are involved in the regulation of HIFa expression and activity, and receptor of activated protein kinase C 1 (RACK1) mediates this process [12,16].…”

Section: Introductionmentioning

confidence: 99%

Endothelin‐1 induces hypoxia inducible factor 1α expression in pulmonary artery smooth muscle cells

Liu

Jin

et al. 2012

FEBS Letters

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Edited by Zhijie Chang Keywords:Endothelin-1 HIF1a Proteasome Calcineurin RACK1 a b s t r a c t Endothelin-1 (ET-1) dose-dependently increased HIF1a expression in pulmonary artery smooth muscle cells (PASMCs). Inhibition of protein synthesis did not affect ET-1-induced HIF1a expression. The maximum effect of ET-1 was similar to that caused by proteasome inhibitor MG132. Further study indicates that ET-1 also dose-dependently stimulated calcineurin activation, specific calcineurin inhibitor cyclosporine A (CsA), abolished ET-1-induced HIF1a elevation, and reversed ET-1-induced RACK1 (receptor of activated protein kinase C 1) de-phosphorylation. Endothelin receptor A was found to specifically mediate the effects of ET-1. To examine whether RACK1 is particularly involved in proteasome-dependent HIF1a degradation, RACK1 was silenced by siRNA transfection. Cells lacking RACK1 exhibited significant elevation of HIF1a protein level. Taken together, our study suggests that ET-1 suppressed proteasome-dependent HIF1a degradation by calcineurin-dependent RACK1 de-phosphorylation.

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“…HIF-1α is subjected to O 2 -dependent modification by the prolyl hydroxylase PHD2, which targets the protein for ubiquitination and proteasomal degradation under normoxic conditions, whereas these events are inhibited under conditions of continuous hypoxia (11,12,17). Cycles of hypoxia and reoxygenation also potently increase HIF-1α protein levels and HIF-1 transcriptional activity (18)(19)(20)(21). HIF-1α activation has been demonstrated in human hearts under conditions of myocardial ischemia and infarction (22) and patients with coronary artery disease who carry genetic polymorphisms at the human HIF1A locus are more likely to present to medical attention with stable angina rather than with myocardial infarction (23) and are less likely to have coronary collaterals (24).…”

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confidence: 99%

Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning

Sarkar¹,

Cai²,

Gupta³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Infarction occurs when myocardial perfusion is interrupted for prolonged periods of time. Short episodes of ischemia and reperfusion protect against tissue injury when the heart is subjected to a subsequent prolonged ischemic episode, a phenomenon known as ischemic preconditioning (IPC). Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to hypoxia/ischemia and is required for IPC. In this study, we performed a cellular and molecular characterization of the role of HIF-1 in IPC. We analyzed mice with knockout of HIF-1α or HIF-1β in Tie2 + lineage cells, which include bone marrow (BM) and vascular endothelial cells, compared with control littermates. Hearts were subjected to 30 min of ischemia and 120 min of reperfusion, either as ex vivo Langendorff preparations or by in situ occlusion of the left anterior descending artery. The IPC stimulus consisted of two cycles of 5-min ischemia and 5-min reperfusion. Mice lacking HIF-1α or HIF-1β in Tie2 + lineage cells showed complete absence of protection induced by IPC, whereas significant protection was induced by adenosine infusion. Treatment of mice with a HIF-1 inhibitor (digoxin or acriflavine) 4 h before Langendorff perfusion resulted in loss of IPC, as did administration of acriflavine directly into the perfusate immediately before IPC. We conclude that HIF-1 activity in endothelial cells is required for acute IPC. Expression and dimerization of the HIF-1α and HIF-1β subunits is required, suggesting that the heterodimer is functioning as a transcriptional activator, despite the acute nature of the response.T he heart requires a constant supply of O 2 for generation of ATP, 95% of which is derived from oxidative phosphorylation (1). Coronary artery stenosis due to an atherosclerotic plaque results in reduced perfusion and myocardial ischemia, especially under conditions of increased myocardial O 2 demand, as occurs when heart work is increased in response to physical exertion or emotional stress. Plaque rupture is a catastrophic event that results in complete arterial occlusion and, within ∼20

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Ca2+/Calmodulin Kinase-dependent Activation of Hypoxia Inducible Factor 1 Transcriptional Activity in Cells Subjected to Intermittent Hypoxia

Cited by 215 publications

References 47 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Endothelin‐1 induces hypoxia inducible factor 1α expression in pulmonary artery smooth muscle cells

Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning

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