Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation

Martin, Falk; Linden, Tobias; Katschinski, Dörthe M.; Oehme, Felix; Flamme, Ingo; Mukhopadhyay, Chinmay K.; Eckhardt, Katrin; Tröger, Juliane; Barth, Sandra; Camenisch, Gieri; Wenger, Roland H.

doi:10.1182/blood-2004-10-3980

Cited by 278 publications

(226 citation statements)

References 56 publications

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“…This is the level of DRI for Cu (0.9 mg/day) plus Cu supplementation (2 mg/day) for humans. It should note that many studies in cultured cells use high levels of Cu, ranging from 100 to 500 μM CuCl 2 or CuSO 4 [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Zhou

Jiang

Kang

2008

Journal of Molecular and Cellular Cardiology

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Previous studies have shown that dietary copper supplementation reversed heart hypertrophy induced by pressure overload in a mouse model. The present study was undertaken to understand the cellular basis of copper-induced regression of cardiac hypertrophy. Primary cultures of neonatal rat cardiomyocytes were treated with phenylephrine at a final concentration of 100 μM in cultures for 48 h to induce cellular hypertrophy. The hypertrophied cardiomyocytes were exposed to copper sulfate at a final concentration of 5 μM in cultures for additional 24 h. This copper treatment reduced the size of the hypertrophied cardiomyocytes, as measured by flow cytometry, protein content in cells, cell volume and cardiomyocyte hypertrophy markers including beta myosin heavy chain protein, skeletal alpha-actin, and atrial natriuretic peptide. Cell cycle analysis and cell sorting of p-histone-3 labeled cardiomyocytes indicated that cell division was not involved in the copper-induced regression of cardiomyocyte hypertrophy. Copper also inhibited PE-induced apoptosis, determined by a TUNEL assay. Because copper stimulates vascular endothelial growth factor (VEGF) production through activation of hypoxia-inducible transcription factor, an anti-VEGF antibody at a final concentration of 2 ng/ml in cultures was used and shown to blunt copper-induced regression of cell hypertrophy. Conversely, VEGF alone at a final concentration of 0.2 μg/ml reversed cell hypertrophy as the same as copper did. This study demonstrates that both copper and VEGF reduce the size of hypertrophied cardiomyocytes, and copper regression of cardiac hypertrophy is VEGF dependent.

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Section: Discussionmentioning

confidence: 99%

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Zhou

Jiang

Kang

2008

Journal of Molecular and Cellular Cardiology

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“…Immunoblot analyses were performed as previously described (Martin et al, 2005). Protein concentrations were determined by the Bradford method.…”

Section: Immunoblottingmentioning

confidence: 99%

Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

Balamurugan

et al. 2009

Oncogene

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The onconeuronal cerebellar degeneration-related antigen Cdr2 is associated with paraneoplastic syndromes. Neoplastic expression of Cdr2 in ovary and breast tumors triggers an autoimmune response that suppresses tumor growth by developing tumor immunity, but culminates in cerebellar degeneration when Cdr2-specific immune cells recognize neuronal Cdr2. We identified Cdr2 as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1 and provide evidence that Cdr2 might represent a novel important tumor antigen in renal cancer. Strong Cdr2 protein expression was observed in 54.2% of papillary renal cell carcinoma (pRCC) compared with 7.8% of clear-cell RCC and no staining was observed in chromophobe RCC or oncocytoma. High Cdr2 protein levels correlated with attenuated HIF target gene expression in these solid tumors, and Cdr2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation. This effect was because of both attenuation of hypoxic protein accumulation and suppression of the transactivation activity of HIF-1a. pRCC is known for its tendency to avascularity, usually associated with a lower pathological stage and higher survival rates. We provide evidence that Cdr2 protein strongly accumulates in pRCC, attenuates the HIF response to tumor hypoxia and may become of diagnostic importance as novel renal tumor marker.

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“…For instance, they are sensitive to changes in ascorbate, nitric oxide and transition metal levels [34][35][36][37]. In addition, the PHDs themselves might provide the molecular link between mitochondrial function and HIFα regulation:…”

Section: Links Between Mitochondria and The Phd Oxygen Sensorsmentioning

confidence: 99%

Mitochondria: Oxygen sinks rather than sensors?

Wenger

2006

Medical Hypotheses

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At the cellular level, oxygen partial pressure (pO2) is sensed by a family of protein hydroxylases. These enzymes transmit the information about the current pO2 directly to hypoxia-inducible transcription factors (HIFs) in the form of covalently attached hydroxy groups which regulate abundance and activity of the HIFs. In addition to this highly specific and direct mechanism of oxygen sensing, mitochondria were repeatedly proposed to sense oxygen and to transmit the signal in the form of a side product of the electron transport chain, i.e. the reactive oxygen species (ROS). However, the exact correlation between pO2 and ROS production, the precise downstream targets of ROS, and how ROS regulate these targets at the molecular level, are questions that remain unanswered. Supported by recent novel data, an alternative model is discussed which is based on the redirection of oxygen towards the protein hydroxylase oxygen sensors. Under conditions of changes in oxygen usage, e.g. following changes in mitochondrial function or cellular metabolism, oxygen redirection would provide an elegant explanation for HIF regulation under apparently constant external oxygen concentrations. SummaryAt the cellular level, oxygen partial pressure (pO 2 ) is sensed by a family of protein hydroxylases. These enzymes transmit the information about the current pO 2 directly to hypoxia-inducible transcription factors (HIFs) in the form of covalently attached hydroxy groups which regulate abundance and activity of the HIFs. In addition to this highly specific and direct mechanism of oxygen sensing, mitochondria were repeatedly proposed to sense oxygen and to transmit the signal in the form of a side product of the electron transport chain, i.e. the reactive oxygen species (ROS). However, the exact correlation between pO 2 and ROS production, the precise downstream targets of ROS, and how ROS regulate these targets at the molecular level, are questions that remain unanswered. Supported by recent novel data, an alternative model is discussed which is based on the redirection of oxygen towards the protein hydroxylase oxygen sensors. Under conditions of changes in oxygen usage, e.g. following changes in mitochondrial function or cellular metabolism, oxygen redirection would provide an elegant explanation for HIF regulation under apparently constant external oxygen concentrations. 3 Oxygen sensing in health and diseaseThe transcriptional regulator hypoxia-inducible factor (HIF) is central to physiological and pathological processes involved in the adaptation to decreased oxygen availability. More than 70 direct target genes are known up to date and expression of probably far more than 200 genes is directly or indirectly increased by HIF [1,2]. Understanding this orchestrated response to low oxygen is important to medical progress because many major diseases of developed countries, including solid tumor growth, stroke, infarction, microbial infections, rheumatoid arthritis and chronic ulcerations, are associated with impaired oxygen suppl...

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Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation

Cited by 278 publications

References 56 publications

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

Mitochondria: Oxygen sinks rather than sensors?

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