Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1

Manalo, Dominador J.; Rowan, Ashley; Lavoie, Tera; Natarajan, Lakshmi; Kelly, Brian; Ye, Shui Q.; Garcia, Joe G.N.; Semenza, Gregg L.

doi:10.1182/blood-2004-07-2958

Cited by 1,005 publications

(860 citation statements)

References 55 publications

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“…Previous work with non-RCC cells has indicated that although the large majority of hypoxia inducible genes are responsive to HIF-1a (Hu et al, 2003;Park et al, 2003;Sowter et al, 2003;Manalo et al, 2005;Wang et al, 2005), two distinct patterns of response are observed with some genes being exclusively responsive to HIF-1a and some responding to both HIF-1a and HIF-2a. In RCC cells, this transcriptional selectivity is more marked with the former group of genes remaining exclusively responsive to HIF-1a and the latter becoming dominantly, or even exclusively, responsive to HIF-2a (Sowter et al, 2003;Raval et al, 2005).…”

Section: Resultsmentioning

confidence: 98%

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Lau¹,

Tian²,

Raval³

et al. 2007

Br J Cancer

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Inactivation of the von Hippel -Lindau tumour suppressor in renal cell carcinoma (RCC) leads to failure of proteolytic regulation of the a subunits of hypoxia-inducible factor (HIF), constitutive upregulation of the HIF complex, and overexpression of HIF target genes. However, recent studies have indicated that in this setting, upregulation of the closely related HIF-a isoforms, HIF-1a and HIF-2a, have contrasting effects on tumour growth, and activate distinct sets of target genes. To pursue these findings, we sought to elucidate the mechanisms underlying target gene selectivity for HIF-1a and HIF-2a. Using chromatin immunoprecipitation to probe binding to hypoxia response elements in vivo, and expression of chimaeric molecules bearing reciprocal domain exchanges between HIF-1a and HIF-2a molecules, we show that selective activation of HIF-a target gene expression is not dependent on selective DNAbinding at the target locus, but depends on non-equivalent C-terminal portions of these molecules. Our data indicate that post-DNA binding mechanisms that are dissimilar for HIF-1a and HIF-2a determine target gene selectivity in RCC cells.

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Section: Resultsmentioning

confidence: 98%

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Lau¹,

Tian²,

Raval³

et al. 2007

Br J Cancer

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“…A broad range of genes that are implicated in events such as angiogenesis, cell survival/death, metabolism, pH regulation, adhesion, extracellular matrix remodeling, migration and metastasis are targeted [12,15,17,18]. The functional consequences of enhanced expression of a small selection of some of these gene products are discussed below (Fig.…”

Section: The Hif-mediated Cellular Responsementioning

confidence: 99%

Hypoxia and cancer

2007

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A major feature of solid tumours is hypoxia, decreased availability of oxygen, which increases patient treatment resistance and favours tumour progression. How hypoxic conditions are generated in tumour tissues and how cells respond to hypoxia are essential questions in understanding tumour progression and metastasis. Massive tumour-cell proliferation distances cells from the vasculature, leading to a deficiency in the local environment of blood carrying oxygen and nutrients. Such hypoxic conditions induce a molecular response, in both normal and neoplastic cells, that drives the activation of a key transcription factor; the hypoxia-inducible factor. This transcription factor regulates a large panel of genes that are exploited by tumour cells for survival, resistance to treatment and escape from a nutrient-deprived environment. Although now recognized as a major contributor to cancer progression and to treatment failure, the precise role of hypoxia signalling in cancer and in prognosis still needs to be further defined. It is hoped that a better understanding of the mechanisms implicated will lead to alternative and more efficient therapeutic approaches.

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“…Under hypoxia, HIF-1a subunit is stabilized and dimerizes with HIF-1b, translocates to the nucleus, and activates transcription of target genes via binding to hypoxia-responsive elements (HREs) [22,28]. HIF-1 induces the expression of more than 100 genes [29], including the vascular endothelial growth factor (VEGF), glycolytic enzymes [30], and various genes involved in proliferation and cell cycle progression, to insure the cancer cell survival [20,31,32]. Recently, the HIF-1 role as a repressor in response to hypoxia has been shown in several tumors.…”

Section: Introductionmentioning

confidence: 99%

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Fanale

Bazan

Corsini

et al. 2013

Breast Cancer Res Treat

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Numerous microarray-based gene expression studies performed on several types of solid tumors revealed significant changes in key genes involved in progression and regulation of the cell cycle, including AURKA that is known to be overexpressed in many types of human malignancies. Tumor hypoxia is associated with poor prognosis in several cancer types, including breast cancer (BC). Since hypoxia is a condition that influences the expression of many genes involved in tumorigenesis, proliferation, and cell cycle regulation, we performed a microarray-based gene expression analysis in order to identify differentially expressed genes in BC cell lines exposed to hypoxia. This analysis showed that hypoxia induces a down-regulation of AURKA expression. Although hypoxia is a tumor feature, the molecular mechanisms that regulate AURKA expression in response to hypoxia in BC are still unknown. For the first time, we demonstrated that HIF-1 activation downstream of hypoxia could drive AURKA down-regulation in BC cells. In fact, we found that siRNA-mediated knockdown of HIF-1a significantly reduces the AURKA down-regulation in BC cells under hypoxia. The aim of our study was to obtain new insights into AURKA transcriptional regulation in hypoxic conditions. Luciferase reporter assays showed a reduction of AURKA promoter activity in hypoxia. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1, rather than inducing transcriptional activation, could promote the AURKA down-regulation via its binding to hypoxia-responsive elements into the proximal region of the AURKA promoter. The present study shows that hypoxia directly links HIF-1 with AURKA expression, suggesting a possible pathophysiological role of this new pathway in BC and confirming HIF-1 as an important player linking an environmental signal to the AURKA promoter. Since AURKA down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells, these findings could be important for the development of new possible therapies against BC.

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Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1

Cited by 1,005 publications

References 55 publications

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Hypoxia and cancer

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

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