Functional genomics approach to hypoxia signaling

Seta, Karen A.; Millhorn, David E.

doi:10.1152/japplphysiol.00836.2003

Cited by 54 publications

(43 citation statements)

References 81 publications

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“…Different inhibitors were used to identify the signaling pathways involved in hypoxia-induced UII expression (Seta & Millhorn 2004). Polyclonal antibodies against JNK and mAbs against phospho-JNK were obtained from Cell Signaling (Beverly, MA, USA).…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

“…In response to hypoxia, the heart also generates ROS, resulting in cardiac hypertrophy and expression of fetal cardiac genes (Inamoto et al 2006, Kontaraji et al 2007, Yamashita et al 2007) through various signaling cascades (Seta & Millhorn 2004). A previous study has shown that the density of binding sites for UII in sarcolemma of the myocardium increased in rats exposed to chronic hypoxia (Zhang et al 2002).…”

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confidence: 99%

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Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

Chiu¹,

Wang²,

Shyu³

2014

Journal of Endocrinology

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Cardiomyocyte hypoxia causes cardiac hypertrophy through cardiac-restricted gene expression. Urotensin II (UII) cooperates with activating protein 1 (AP1) to regulate cardiomyocyte growth in response to myocardial injuries. Angiotensin II (AngII) stimulates UII expression, reactive oxygen species (ROS) production, and cardiac hypertrophy. This study aimed to evaluate the expression of UII, ROS, and AngII as well as their genetic transcription after hypoxia treatment in neonatal cardiomyocytes. Cultured neonatal rat cardiomyocytes were subjected to hypoxia for different time periods. UII (Uts2) protein levels increased after 2.5% hypoxia for 4 h with earlier expression of AngII and ROS. Both hypoxia and exogenously added AngII or Dp44mT under normoxia stimulated UII expression, whereas AngII receptor blockers, JNK inhibitors (SP600125), JNK siRNA, or N-acetyl-L-cysteine (NAC) suppressed UII expression. The gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between UII and AP1. The luciferase assay confirmed an increase in transcription activity of AP1 to the UII promoter under hypoxia. After hypoxia, an increase in 3 H-proline incorporation in the cardiomyocytes and expression of myosin heavy chain protein, indicative of cardiomyocyte hypertrophy, were observed. In addition, hypoxia increased collagen I expression, which was inhibited by SP600125, NAC, and UII siRNA. In summary, hypoxia in cardiomyocytes increases UII and collagen I expression through the induction of AngII, ROS, and the JNK pathway causing cardiomyocyte hypertrophy and fibrosis.

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Section: Antibodies and Reagentsmentioning

confidence: 99%

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confidence: 99%

Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

Chiu¹,

Wang²,

Shyu³

2014

Journal of Endocrinology

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confidence: 99%

Understanding Hypoxia-Induced Gene Expression in Early Development: In Vitro and In Vivo Analysis of Hypoxia-Inducible Factor 1-Regulated Zebra Fish Insulin-Like Growth Factor Binding Protein 1 Gene Expression

Kajimura

Aida

Duan

2006

Molecular and Cellular Biology

138

106

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Hypoxia triggers the transcription of regulatory genes that promote O 2 delivery and anaerobic metabolism, suppress major energy-requiring processes, and inhibit growth and development in animals ranging from invertebrates to mammals (14,15,40). Hypoxia also influences several human pathological processes, such as tumorigenesis and intrauterine growth restriction (IUGR). The majority of these transcriptional responses to hypoxia are mediated by the hypoxia-inducible factor 1 (HIF-1) complex. HIF-1 is a heterodimeric complex composed of 45). HIF-1␤, also known as aryl hydrocarbon receptor nuclear translocator, is constitutively expressed and insensitive to O 2 availability. When oxygen levels are high, HIF-1␣ is bound to the von Hippel-Lindau tumor suppressor (pVHL) and targeted for ubiquitination and proteosomal degradation (30, 34). Hypoxic conditions inhibit this degradation, which allows HIF-1␣ to accumulate in the cell (16,18,27). HIF-1␣ is then translocated to the nucleus, dimerizes with HIF-1␤, binds to DNA, and activates target gene expression (3). Hypoxia response elements (HREs) are cis-regulatory DNA sequences that specifically bind to HIF-1 and are required for transcriptional induction upon hypoxia exposure.Insulin-like growth factor binding protein 1 (IGFBP-1) is a hypoxia-inducible gene. Earlier studies have shown that circulating levels of IGFBP-1 are elevated in IUGR fetuses (7,12,42,43). In vitro studies using cultured human cells and in vivo studies using rodent and fish models suggest that IGFBP-1 gene expression is elevated under hypoxic conditions (13,29,31,35,41). Since IGFBP-1 binds IGFs and inhibits IGF action on cell growth in vitro (4, 9) and because IGFBP-1 overexpression reduced birth weights in mice (5,11,36), it was postulated that elevated IGFBP-1 plays a major role in hypoxia-induced IUGR by binding IGFs and inhibiting their growth-promoting activities (41). Using the transparent and free-living zebra fish embryo as a model system, we have recently shown that (i) hypoxia strongly up-regulates IGFBP-1 expression and delays growth and developmental rate in zebra fish embryos; (ii) IGFBP-1 knockdown partially abrogates these hypoxic effects, whereas IGFBP-1 overexpression decreases growth and developmental rates under normoxia; and (iii) reintroduction of IGFBP-1 to the knocked down embryos restores the hypoxic effects (19). These findings provide strong evidence arguing that up-regulation of IGFBP-1 by hypoxia plays a key role in coordinating embryonic growth rate and developmental timing in response to environmental oxygen availability. Although there is in vitro evidence that overexpression of HIF-1␣ in cultured human hepatoma (HepG2) cells increases human IGFBP-1 promoter activity (41), how hypoxia triggers IGFBP-1 gene expression in vivo is not clear, and the cis-regulatory elements responsible for hypoxia-induced IGFBP-1 transcription in vivo are not well defined.The objectives of this study are (i) to determine when the HIF-1 pathway becomes operational in early development and

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“…This finding may be associated with the effects of hypoxia and ischemia occurring in the melanoma microenvironment (23,24). In this type of microenvironment, tumor cells can secrete certain proteins or upregulate expression of specific proteins in order to adapt to the poor conditions (25,26).…”

Section: Discussionmentioning

confidence: 99%

Influence of microenvironments on microcirculation patterns and tumor invasion-related protein expression in melanoma

et al. 2009

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Abstract. This study aimed to investigate the influence of different microenvironments on melanoma microcirculation patterns, invasiveness and metastatic behavior. Sixty C57BL/6J mice were randomly divided into two groups with 30 mice per group. Melanoma B16 cells were injected into the subretinal space and groin area of mice synchronously. The number of each type of microcirculation pattern was counted. Invasion and metastasis were observed. Epithelial cell kinase (EphA2), matrix metalloproteinase (MMP)-2 and -9 expression and their mRNA levels were detected by immunohistochemical staining and real-time PCR and compared between the two groups. Five invasions and six lung metastases were found in the subretinal group while no invasion and metastasis were found in the groin group. The number of vasculogenic mimicry (VM) was significantly higher in the subretinal group (P=0.000). However, no significant difference in the numbers of mosaic and endothelium-dependent vessels was observed between the two groups (P=0.076 and 0.146, respectively). EphA2, MMP-2 and MMP-9 expression was significantly higher in the subretinal group. The mRNA levels of EphA2, MMP-2 and MMP-9 were slightly higher in the subretinal tumors (P=0.002, 0.001 and 0.001, respectively). In conclusion, this experimental paradigm can be a powerful one in which to investigate tumor-microenvironment interactions in melanoma. Tumor cells in the intraocular microenvironment had increased EphA2 expression which induced the formation of VM channels. Moreover, expression of MMP-2 and -9 in tumor tissue was increased to enhance the invasiveness and metastatic behavior.

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Functional genomics approach to hypoxia signaling

Cited by 54 publications

References 81 publications

Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

Understanding Hypoxia-Induced Gene Expression in Early Development: In Vitro and In Vivo Analysis of Hypoxia-Inducible Factor 1-Regulated Zebra Fish Insulin-Like Growth Factor Binding Protein 1 Gene Expression

Influence of microenvironments on microcirculation patterns and tumor invasion-related protein expression in melanoma

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