Synergistic Cooperation between Hypoxia and Transforming Growth Factor-β Pathways on Human Vascular Endothelial Growth Factor Gene Expression

Sánchez-Elsner, Tilman; Botella, Luisa María; Velasco, Beatriz; Corbí, Ángel L.; Attisano, Liliana; Bernabéu, Carmelo

doi:10.1074/jbc.m104536200

Cited by 354 publications

(273 citation statements)

References 74 publications

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“…However, increased promoter activity was observed in response to hypoxia in these constructs, confirming the presence of functional HRE sites that could positively regulate promoter activity without the requirement for TGF-␤ 1 signaling. Although a synergistic increase in Ctgf promoter activity in response to combined TGF-␤ 1 and hypoxic stimulation was not observed in our reporter assays, we cannot disregard the possibility that these two factors may act synergistically, as in the case of VEGF mRNA regulation (53). Because our reporter assays were terminated after 12 h of stimulation, it is possible that longer stimulation past 24 h may reveal synergism of these two factors.…”

Section: Discussionmentioning

confidence: 75%

Hypoxic induction ofCtgfis directly mediated by Hif-1

Higgins

Biju²,

Akai³

et al. 2004

American Journal of Physiology-Renal Physiology

257

196

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CTGF plays a significant role in the development of renal fibrosis by mediating the fibrotic effects of transforming growth factor (TGF)-β1and has been shown to be hypoxia inducible in human breast cancer cells. It has been suggested that hypoxia is an important underlying cause for the development of renal fibrosis through the modulation of profibrotic genes. One of the key mediators of the cell's response to lowered oxygen environments is hypoxia-inducible-factor-1 (HIF-1), a basic helix-loop-helix transcription factor, which enables cells to adapt to hypoxia by regulating the expression of genes involved in increasing oxygen availability ( VEGF, erythropoietin) and enhancing glucose uptake and metabolism ( Glut-1, PGK). In this paper, we have used primary tubular epithelial cell cultures from a tetracycline-inducible- Hif- 1α knockout murine model to further elucidate the role of Hif-1 in the hypoxic-induction of Ctgf expression. We show that hypoxia response elements present upstream of Ctgf enable direct interaction of Hif-1 transcription factor with the Ctgf promoter, resulting in increased transcription of Ctgf mRNA. Cells deficient in Hif- 1α were incapable of inducing Ctgf mRNA in response to hypoxia, suggesting an absolute requirement of Hif-1. Furthermore, the observed Hif-1-mediated hypoxic stimulation of Ctgf expression was found to occur independently of TGF-β1signaling. Our findings have important implications for a number of fibrotic disorders in which hypoxia, CTGF, and TGF-β1are involved, including renal, dermal, hepatic, and pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 75%

Hypoxic induction ofCtgfis directly mediated by Hif-1

Higgins

Biju²,

Akai³

et al. 2004

American Journal of Physiology-Renal Physiology

257

196

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“…64 HIF-1a was shown to interact with Smad3 in vivo, and to bind synergistically with HIF-1 to a Smad-binding site near the HRE in the VEGF promoter. 65 As Smad3 was previously shown to interact with CBP/p300, a possible mechanism for the enhancement of VEGF transcription by Smad3 may be through stabilisation of the HIF-1a-CBP/p300 interaction on the DNA. Additionally, STAT3 was found to be important for maximal VEGF expression in complex with HIF-1 and CBP/p300 in prostate and pancreatic carcinoma.…”

Section: Other Modifications Affecting Hif-driven Transcriptionmentioning

confidence: 99%

Turn me on: regulating HIF transcriptional activity

2008

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The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

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“…4A). Another intriguing observation is that SMAD3/4 and HIF-1a have been shown to assemble into a same protein complex, which is responsible for transcriptional activation of different genes under hypoxia (24,25). Thus, deletion of Smad4 in BxPC-3 pancreatic cancer cells could explain the moderate induction of 4E-BP1 protein expression under hypoxia.…”

Section: Ref 23)mentioning

confidence: 97%

Contribution of HIF-1α in 4E-BP1 Gene Expression

Azar

Lasfargues

Bousquet

et al. 2013

Molecular Cancer Research

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The eukaryotic translation initiation factor 4E (eIF4E) is necessary for the translation of capped mRNAs into proteins. Cap-dependent mRNA translation can be however inhibited by the eIF4E-binding protein 1 (4E-BP1). The hypophosphorylated forms of 4E-BP1 indeed sequester eIF4E and thus block translation initiation and consequent protein synthesis. Different reports indicate that, in addition to hypophosphorylation, 4E-BP1 function can be also regulated at the level of protein expression. This is the case in contact-inhibited cells or in cells exposed to hypoxia. The molecular mechanisms responsible for 4E-BP1 protein accumulation in these conditions remain however unknown. In the present study, we found that 4E-BP1 gene promoter contains a hypoxia-responsive element (HRE) that mediates 4E-BP1 gene upregulation via the hypoxia-inducible factor-1 alpha (HIF-1a) transcription factor. Gene reporter assays then revealed that the presence of such HRE in the promoter of 4E-BP1 gene is involved in 4E-BP1 accumulation in contact-inhibited cells and in cells exposed to hypoxia. We also reveal that the TGF-b-dependent transcription factor SMAD4 cooperates with HIF-1a to fully activate 4E-BP1 gene transcription under hypoxia. These data therefore suggest that HIF-1a contributes to 4E-BP1

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Synergistic Cooperation between Hypoxia and Transforming Growth Factor-β Pathways on Human Vascular Endothelial Growth Factor Gene Expression

Cited by 354 publications

References 74 publications

Hypoxic induction ofCtgfis directly mediated by Hif-1

Hypoxic induction ofCtgfis directly mediated by Hif-1

Turn me on: regulating HIF transcriptional activity

Contribution of HIF-1α in 4E-BP1 Gene Expression

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