<i>Review:</i>Hypoxia-Inducible Factor-1 (HIF-1): A Novel Transcription Factor in Immune Reactions

Hellwig-Bürgel, Thomas; Stiehl, Daniel P.; Wagner, Anika E.; Metzen, Eric; Jelkmann, Wolfgang

doi:10.1089/jir.2005.25.297

Cited by 239 publications

(220 citation statements)

References 154 publications

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“…A positive feedback regulation between MMP-9 and VEGF was reported in retinal pigment epithelial cells (Hollborn et al, 2007). Our PCR array analysis also indicates that MMP-9 induction induced HIF expression (Supplementary Figure 1), a transcriptional factor for VEGF (Hellwig-Burgel et al, 2005) that probably induced VEGF levels.…”

Section: Discussionsupporting

confidence: 75%

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

et al. 2010

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BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC), a matricellular glycoprotein, modulates cellular interaction with the extracellular matrix and is capable of altering the growth of various cancers. We therefore sought to determine the effect of SPARC expression on medulloblastoma tumour growth and angiogenesis. METHODS: To this extent, we selected three SPARC full-length cDNA overexpressed clones (Daoy-SP). Consequences of SPARC overexpression were studied in terms of cell growth, angiogenesis using co-culture assay in vitro, dorsal skin-fold chamber assay in vivo, PCR Array for human angiogenic genes, as well as western blotting for angiogenic molecules and tumour growth, in an orthotopic tumour model. RESULTS: The SPARC protein and mRNA levels were increased by approximately three-fold in Daoy-SP cells compared with parental (Daoy-P) and vector (Daoy-EV) controls. Daoy-SP clones reduced tumour cell-induced angiogenesis in vitro and in vivo, and formed small tumours with fewer blood vessels when compared with controls. Matrix metalloprotease-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression were decreased in Daoy-SP clones. Further, inhibition of MMP-9 expression caused SPARCmediated inhibition of angiogenesis and tumour growth as MMP-9 rescued SPARC-mediated anti-angiogenic effect in vitro and tumour growth inhibition in vivo. CONCLUSION: Overexpression of SPARC decreases angiogenesis, which leads to decreased tumour growth. Further, the role of MMP-9 could be attributed to the anti-angiogenic effect of SPARC.

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Section: Discussionsupporting

confidence: 75%

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

et al. 2010

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“…Thus, HIF target gene activation may be an early event, occurring as part of an adaptive response accompanying ␤-cell mass expansion, taking place prior to overt diabetes, at least in rodent models. Importantly, many other signals including growth factors, hormones, and inflammatory cytokines such as TNF␣ are potent activators of HIF under normoxia (Cramer et al 2003;Hellwig-Burgel et al 2005). For example, TNF␣ is released by macrophages that populate the adipose tissue in obese states (Coppack 2001).…”

Section: Pvhl-hif Regulates Insulin Secretion Genes and Development 3141mentioning

confidence: 99%

“…Finally, in addition to the well-established activation of HIF␣ in response to oxygen availability, there is accumulating evidence for hypoxia-independent mechanisms of HIF1␣ expression. For example, high levels of HIF1␣ expression have been observed under well-oxygenated conditions in response to growth factor stimulation (Hellwig-Burgel et al 2005). Growth factor-mediated up-regulation of HIF1␣ expression has been implicated to promote glucose uptake and a form of metabolism that is referred to as "aerobic glycolysis" to better meet the bioenergetic needs associated with growth and proliferation (Lum et al 2007).…”

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confidence: 99%

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Zehetner¹,

Danzer²,

Collins³

et al. 2008

Genes Dev.

108

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Insulin secretion from pancreatic ␤ cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1␣, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1␣ pathway in the control of ␤-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in ␤ cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca 2+ concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1␣ rescued these phenotypes, implying that they are the result of HIF1␣ activation. Together, these results identify pVHL and HIF1␣ as key regulators of insulin secretion from pancreatic ␤ cells. They further suggest that changes in the metabolic strategy of glucose metabolism in ␤ cells have profound effects on whole-body glucose homeostasis.[Keywords: HIF; VHL; glucose intolerance; islet; pancreas] Supplemental material is available at http://www.genesdev.org. Received July 14, 2008; revised version accepted September 5, 2008. During adulthood, cell type-specific growth that exceeds the normal physiological constraints is a common feature of adaptive processes of tissues to changes in metabolic homeostasis and underlies the development of many human diseases, including cancer, heart disease, and diabetes (De Boer et al. 2003;Bouwens and Rooman 2005). Adaptive cell mass expansion, whether neoplastic or nonneoplastic, creates a requirement for compensatory neovascularization to supply oxygen, metabolic substances, and growth/survival factors to the growing tissue (Marti 2005). Therefore, adaptive cell growth responses are generally accompanied, at least initially, by relative states of hypoxia as a result of a mismatch between oxygen demand caused by tissue expansion and oxygen supply provided by the vasculature. An immediate consequence of decreased tissue oxygen availability is that cells shift cellular fuel metabolism from mitochondrial respiration to glycolysis and activate an angiogenic program to increase oxygen delivery in order to overcome the imbalance between tissue mass and vascularization (Semenza 2001;Brahimi-Horn et al. 2007). In this way, tissue function is supported and further mass expansion can occur.At the molecular level, the central regulators of the cellular response to low-oxygen availability are the hypoxia-inducible transcription factors (HIF). HIF are heterodimeric transcription factors composed of HIF1␣, HIF2␣, or HI...

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“…After the discovery of HIF1 (Wang and Semenza 1995), cellular responses to hypoxia and their importance have been found in the many fields, including oncogenesis, reproductive physiology, development Wenger 2002;Bruick 2003;Wiesener and Maxwell 2003;Lee et al 2004;Hellwig-Burgel et al 2005;Chen et al 2009;Dunwoodie 2009). The expression of HIF has been found in a variety of organs and the function of some of these HIFs have been determined, which suggests that the cells in such organs have the ability to respond to hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Cellular response to hypoxic conditions are strongly influenced by hypoxia-inducible factors (HIFs). HIFs are hypoxia-specific transcription factors that have roles in inducing several physiological processes including angiogenesis, erythropoiesis and glycolysis (Wiesener and Maxwell 2003;Hellwig-Burgel et al 2005). This review focuses on studies of the roles of hypoxic conditions in the regulation of ovarian function, with emphasis on luteal formation and regression.…”

Section: Introductionmentioning

confidence: 99%

Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase

Nishimura

Okuda

2016

Reprod. Fertil. Dev.

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Promotion of Science (JSPS). 2 Abstract.There is increasing interest in the role of oxygen conditions in the microenvironment of organs, since the discovery of a hypoxia-specific transcription factor, hypoxia-inducible factor-1 (HIF1). Ovarian function has several phases that change day by day, including ovulation, follicular growth, corpus luteum formation and regression. These phases are regulated by many factors, such as pituitary hormones and local hormones including steroids, peptides and cytokines, as well as oxygen conditions. Hypoxia strongly induces angiogenesis because transcription of a potent angiogenic factor, vascular endothelial growth factor, is regulated by HIF1. Follicular development and luteal formation are accompanied by a drastic increase of angiogenesis assisted by the HIF1-VEGF signaling. Hypoxia is also one of the factors for inducing luteolysis by suppressing progesterone synthesis and by promoting apoptosis of luteal cells. This review focuses on recent studies for hypoxic conditions as well as HIF1-regulated genes and proteins in the regulation of ovarian function. Additional keywords Hypoxia, hypoxia-inducible factor IntroductionOvarian function has several phases that change day by day, including follicular growth, ovulation, luteal formation and regression. Follicles progress to ovulation through the proliferation of granulosa and theca cells. After ovulation, the corpus luteum (CL) develops accompanied by active angiogenesis, and when conception does not occur, regresses with the 3 decrease of progesterone (P4) synthesis and apoptosis of luteal cells. During the ovarian cycle, blood flow to the ovary changes, and affects the regulation of ovarian cycles Niswender et al. 1976;Ford and Chenault 1981;Wise et al. 1982;Magness et al. 1983;Acosta et al. 2002). Changes in ovarian blood flow result in the changes in the transport of nutrients, hormones and gases, including O2 to the ovary. In cows, ovarian blood flow has been reported to decrease during luteal regression, and to be kept at low levels during luteal formation after ovulation (Wise et al. 1982). Since a dominant follicle progress to ovulation during luteal regression (McCracken et al. 1999), follicular growth before ovulation occurs in parallel with the decrease of blood flow to the ovary. Furthermore, the oxygen content in ovarian venous blood begins to decrease at the late luteal stage (Wise et al. 1982). These findings indicate that the low oxygen condition (hypoxia) caused by the decreased blood supply is a characteristic part of the ovarian environment during follicular growth, ovulation and luteal formation. as VEGF (Forsythe et al. 1996; Kimura et al. 2001), endothelial nitric oxide synthase (eNOS) (Coulet et al. 2003), and heme oxygenase-1 (HOX-1) (Lee et al. 1997). VEGF stimulates angiogenesis and increases the permeability of blood vessels (Ferrara et al. 2003). eNOS and HOX-1 generate NO and carbon monoxide, which are potent vasodilatory substances that augment perfusion of the hypoxic tissue. At the cellular leve...

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Review:Hypoxia-Inducible Factor-1 (HIF-1): A Novel Transcription Factor in Immune Reactions

Cited by 239 publications

References 154 publications

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase

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