Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway

Ameri, Kurosh; Hammond, Ester M.; Culmsee, Carsten; Raida, Martin; Katschinski, Dörthe M.; Wenger, Roland H.; Wagner, Ernst; Davis, Roger J.; Hai, Tsonwin; Denko, Nicholas C.; Harris, Adrian L.

doi:10.1038/sj.onc.1209781

Cited by 71 publications

(48 citation statements)

References 41 publications

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“…We chose four genes from this list for validation by real-time PCR; two of these, EDN-1 and VEGFR-1, were chosen because they were known to be HIF responsive (HIF-1a/HIF-1b heterodimer) and up-regulated by hypoxia in the lung (21,22). Two further genes, ATF3 and FST, were chosen because they were known to be CREB responsive, but had not previously been shown to be HIF responsive (23,24). In the data presented here, all four of these exemplary genes showed significant increases in expression early in the time course of hypoxic exposure ( Figure 4), confirming these important responses in vivo.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

Leonard

Howell

Madden

et al. 2008

Am J Respir Crit Care Med

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Rationale: Pulmonary hypertension is a common complication of chronic hypoxic lung diseases and is associated with increased morbidity and reduced survival. The pulmonary vascular changes in response to hypoxia, both structural and functional, are unique to this circulation. Objectives: To identify transcription factor pathways uniquely activated in the lung in response to hypoxia. Methods: After exposure to environmental hypoxia (10% O 2 ) for varying periods (3 h to 2 wk), lungs and systemic organs were isolated from groups of adult male mice. Bioinformatic examination of genes the expression of which changed in the hypoxic lung (assessed using microarray analysis) identified potential lung-selective transcription factors controlling these changes in gene expression. In separate further experiments, lung-selective activation of these candidate transcription factors was tested in hypoxic mice and by comparing hypoxic responses of primary human pulmonary and cardiac microvascular endothelial cells in vitro. Measurements and Main Results: Bioinformatic analysis identified cAMP response element binding (CREB) family members as candidate lung-selective hypoxia-responsive transcription factors. Further in vivo experiments demonstrated activation of CREB and activating transcription factor (ATF)1 and up-regulation of CREB family-responsive genes in the hypoxic lung, but not in other organs. Hypoxia-dependent CREB activation and CREB-responsive gene expression was observed in human primary lung, but not cardiac microvascular endothelial cells. Conclusions: These findings suggest that activation of CREB and AFT1 plays a key role in the lung-specific responses to hypoxia, and that lung microvascular endothelial cells are important, proximal effector cells in the specific responses of the pulmonary circulation to hypoxia.Keywords: hypoxia; cAMP response element binding; pulmonary hypertension; transcription factor binding site Pulmonary hypertension is a common complication of chronic hypoxic lung diseases, which is associated with increased morbidity and reduced survival. Moreover, cor pulmonale is an independent predictor of increased mortality, suggesting that pulmonary hypertension contributes directly to reduced survival (1, 2). The increased pulmonary vascular resistance underlying chronic hypoxic pulmonary hypertension is accompanied by characteristic changes in the blood vessels, which include remodeling and thickening of the walls of precapillary vessels and sustained vasoconstriction (3-8). These long-term structural and functional changes in the pulmonary vessels in response to hypoxia are unique to this circulation, and are not observed in the vasculature of other organs of the body.The important roles of the vascular endothelium in the local control of vascular smooth muscle tone and in modulating changes in the structure of the vessel wall are now well recognized (9). It is also well recognized that endothelial cells from different organs show considerable heterogeneity, and that their roles in the control ...

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Section: Discussionmentioning

confidence: 99%

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

Leonard

Howell

Madden

et al. 2008

Am J Respir Crit Care Med

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“…HIF-1α. null MEFs and HIF-1β deficient (Hepa-1C4) cell lines were obtained as in [9]. To achieve <0.01% oxygen, cells were treated as in [10].…”

Section: Cells and Treatmentsmentioning

confidence: 99%

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

Johnson¹,

Denko²,

Barton³

2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

235

207

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Tumor cells respond to the harsh hypoxic microenvironment, in part, by transcriptional regulation of specific target genes. We found that hypoxia-mediated activation of selected genes occurs amidst widespread repression of transcription that is neither cell type-specific nor HIF-1-dependent. Despite overall repression, hypoxia induces a pool of histone modifications typically associated with transcriptional activation or repression. Chromatin immunoprecipitation analyses showed that this global mixture of hypoxia-modified histones is sorted in a gene-specific manner to correlate with transcriptional response to hypoxia. Exceptions to this were unexpected increases in H3K4me3 levels, typically associated with transcriptional activation, and decreased H3K27me3 levels, generally a marker of transcriptional silencing, at core promoters of both hypoxia-activated andrepressed genes. These data suggest that a novel signature of chromatin modifications is induced under hypoxic stress, which may play a role in gene regulatory switches active in proliferating tumor cells undergoing cycles of hypoxia and reoxygenation.

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“…Overwhelming evidence indicates that the ATF3 mRNA level is not detectable in most cells, but greatly increased by a variety of stress signals, including anoxia (Ameri et al, 2007), hypoxia, DNA damage and carcinogens (Hai et al, 1999;Hai and Hartman, 2001). However, recent literature indicates that some of the signals that can induce ATF3 gene expression do not fit the conventional definition of stress signals (Hai, 2006).…”

Section: Introductionmentioning

confidence: 99%

A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development

2007

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Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP response element-binding family of transcription factors. We present evidence that ATF3 has a dichotomous role in cancer development. By both gain-and loss-of-function approaches, we found that ATF3 enhances apoptosis in the untransformed MCF10A mammary epithelial cells, but protects the aggressive MCF10CA1a cells and enhances its cell motility. Array analyses indicated that ATF3 upregulates the expression of several genes in the tumor necrosis factor pathway in the MCF10A cells but upregulates the expression of several genes implicated in tumor metastasis, including TWIST1, fibronectin (FN)-1, plasminogen activator inhibitor-1, urokinase-type plasminogen activator, caveolin-1 and Slug, in the MCF10CA1a cells. We present evidence that ATF3 binds to the endogenous promoters and regulates the transcription of the TWIST1, FN-1, Snail and Slug genes. Furthermore, conditioned medium experiments indicated that ATF3 has a paracrine/autocrine effect, consistent with its upregulation of genes encoding secreted factors. Finally, ATF3 gene copy number is >2 in B80% of the breast tumors examined (N ¼ 48) and its protein level is elevated in B50% of the tumors. These results provided a correlative argument that it is advantageous for the malignant cancer cells to express ATF3, consistent with its oncogenic roles suggested by the MCF10CA1a cell data.

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Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway

Cited by 71 publications

References 41 publications

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development

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