Cell-specific and hypoxia-dependent regulation of human HIF-3α: inhibition of the expression of HIF target genes in vascular cells

Augstein, Antje; Poitz, David M.; Braun-Dullaeus, Ruediger C.; Strasser, Ruth H.; Schmeißer, Alexander

doi:10.1007/s00018-010-0575-4

Cited by 51 publications

(58 citation statements)

References 55 publications

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“…The double P393A/P493A mutant behaved essentially the same as the P493A single mutant, suggesting that P493 is more critical for Hif-3␣ stability regulating (56). pVHL recognizes human HIF-1␣ at L574, which is required for human HIF-1␣ instability (1). When the corresponding residue in zebrafish Hif-3␣ (L503) is mutated together with P493 and P393, it resulted in a further increase in Hif-3␣ protein levels, suggesting that L503 contributes to the instability of zebrafish Hif-3␣1 under normoxia (56).…”

Section: Regulation Of Hif-3␣ Expression and Activitymentioning

confidence: 86%

“…It was reported that Hif-2␣ mediated hypoxiainduced Hif-3␣ gene expression in murine 3T3-L1 cells (13). Augstein et al (1) showed that human HIF-3␣2 mRNA expression in human umbilical venous endothelial cells (HUVECs) is induced by hypoxia and this hypoxic induction involves both HIF-1␣, HIF-2␣, and other factors. There is also evidence that several hypoxia-inducible miRNAs may mediate the hypoxia-induced HIF-3␣ gene expression (6).…”

Section: Regulation Of Hif-3␣ Expression and Activitymentioning

confidence: 99%

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Hypoxia-inducible factor 3 biology: complexities and emerging themes

Duan

2016

American Journal of Physiology-Cell Physiology

215

172

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Duan C. Hypoxia-inducible factor 3 biology: complexities and emerging themes. Am J Physiol Cell Physiol 310: C260 -C269, 2016. doi:10.1152/ajpcell.00315.2015.-The hypoxia-inducible factor (HIF) family has three distinct members in most vertebrates. All three HIFs consist of a unique and oxygen-labile ␣-subunit and a common and stable ␤-subunit. While HIF-1 and HIF-2 function as master regulators of the transcriptional response to hypoxia, much less is known about HIF-3. The HIF-3␣ gene gives rise to multiple HIF-3␣ variants due to the utilization of different promoters, different transcription initiation sites, and alternative splicing. These HIF-3␣ variants are expressed in different tissues, at different developmental stages, and are differentially regulated by hypoxia and other factors. Recent studies suggest that different HIF-3␣ variants have different and even opposite functions. There is strong evidence that full-length HIF-3␣ protein functions as an oxygen-regulated transcription activator and that it activates a unique transcriptional program in response to hypoxia. Many HIF-3␣ target genes have been identified. While some short HIF-3␣ variants act as dominant-negative regulators of HIF-1/2␣ actions, other HIF-3␣ variants can inhibit HIF-1/2␣ actions by competing for the common HIF-␤. There are also a number of HIF-3␣ variants yet to be explored. Future studies of these naturally occurring HIF-3␣ variants will provide new and important insights into HIF biology and may lead to the development of new therapeutic strategies.hypoxia-inducible factor; alternative splicing; oxygen-dependent degradation; gene expression OXYGEN IS AN ESSENTIAL MOLECULE required for cellular respiration and efficient energy production. Hypoxia, a condition in which an organism or a cell is deprived of adequate oxygen (e.g., when oxygen demand exceeds oxygen supply), occurs in developing embryos and adult tissues and plays key roles in stem cell biology, development, and adult physiology. Hypoxia is also frequently associated with pathological states such as ischemia, arthritis, inflammation, and tumorigenesis. Hypoxia triggers complex adaptive responses and activates the expression of numerous genes. These hypoxia-responsive genes are involved in changes in erythropoiesis, angiogenesis, metabolic reprograming, cell-cycle regulation, and tumorigenesis (9,39,(43)(44)(45). The transcriptional response to hypoxia is coordinated by hypoxiainducible factors (HIFs). HIFs are heterodimers, consisting of an oxygen-labile HIF␣ subunit and a stable HIF-␤ subunit [also known as aryl hydrocarbon receptor nuclear translocator (ARNT)]. In human and other vertebrate species, there are three distinct HIF␣ genes. Much of our knowledge about HIF signaling is derived from studies on HIF-1␣ and HIF-2␣ (9, 39, 43-45). Both HIF-1␣ and HIF-2␣ contain a basic helix-loophelix (bHLH) domain, two Per-Arnt-Sim (PAS) domains, a PAS-associated COOH-terminal (PAC) domain; an oxygendependent degradation (ODD) domain; an NH 2 -terminal transactivation domain (N...

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Section: Regulation Of Hif-3␣ Expression and Activitymentioning

confidence: 86%

Section: Regulation Of Hif-3␣ Expression and Activitymentioning

confidence: 99%

Hypoxia-inducible factor 3 biology: complexities and emerging themes

Duan

2016

American Journal of Physiology-Cell Physiology

215

172

View full text Add to dashboard Cite

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“…HIF-1α and HIF-2α are often overexpressed in cancer tissue, leading to progression of aggressive tumors, tumor resistance to chemotherapy and radiation, and poor prognosis of the disease (14)(15)(16)(17). The role of HIF-3α in tumors types remains to be elucidated, however, previous studies have indicated that HIF-3α may suppress the expression of genes, which are typically inducible by HIF-1α and HIF-2α in tumor cells (13,18). Therefore, HIF-3α has transcriptional regulatory functions and is a negative regulator of gene expression during hypoxia (13,18).…”

Section: Introductionmentioning

confidence: 99%

“…The role of HIF-3α in tumors types remains to be elucidated, however, previous studies have indicated that HIF-3α may suppress the expression of genes, which are typically inducible by HIF-1α and HIF-2α in tumor cells (13,18). Therefore, HIF-3α has transcriptional regulatory functions and is a negative regulator of gene expression during hypoxia (13,18). Furthermore, HIF-3α is a true transcription factor since it actively stimulates the expression of a number of target genes (19).…”

Section: Introductionmentioning

confidence: 99%

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Yang

Xiong

et al. 2015

Molecular Medicine Reports

110

103

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Abstract. Hypoxia inducible factors (HIFs) are transcription factors, which are commonly expressed in mammals, including humans. The HIFs consist of hypoxia-regulated α and oxygen-insensitive β subunits, and are key regulators of gene expression during hypoxia in normal and solid tumor tissues. Three members of the HIF family, HIF-1α, HIF-2α, and HIF-3α, are currently known. HIF-3α differs from HIF-1α and HIF-2α in protein structure and regulation of gene expression. For a long time, HIF-3α was considered as a negative mediator of HIF-regulated genes. HIF-3 has a transcriptional regulatory function, which negatively affects gene expression by competing with HIF-1α and HIF-2α in binding to transcriptional elements in target genes during hypoxia. Previously, certain target genes of HIF-3α have been identified, confirming the role of HIF-3α as a transcription factor. In this review, the protein structure, gene regulation and biological function of HIF-3 are discussed based on the literature.

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“…The marked downregulation of these genes once again provided evidence that inflammation and basement membrane degradation are suppressed in NF1 patients, which may reduce the risk of tumor metastasis. HIF3α acts as a negative regulator of hypoxia, so it may induce the tolerance of the extracellular environment (13). Whether HIF3α is involved in promoting nerve growth remains to be verified.…”

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confidence: 99%

Microarray-based identification of nerve growth-promoting genes in neurofibromatosis type I

Liu

Kang

et al. 2013

Molecular Medicine Reports

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Abstract. As a genetic disease, neurofibromatosis type 1 (NF1) is characterized by abnormalities in multiple tissues derived from the neural crest, including neoplasms in the ends of the limbs. The exact mechanism of nerve growth in NF1 is unclear. In the present study, the gene expression profile of nerves in healthy controls and NF1 patients with macrodactylia of the fingers or toes were analyzed in order to identify possible genes associated with nerve growth. The Whole Human Genome Microarray was selected to screen for different gene expression profiles, and the result was analyzed with Feature Extraction software. The target genes were verified at the transcriptional and translational levels by reverse transcription-polymerase chain reaction and western blotting, respectively. A common set of 28 genes were identified to be changed >5-fold in the NF1 patients compared with the healthy controls. Among them, the metastasis-associated genes, lymphocyte function-associated antigen 1, C-X-C chemokine receptor type 4 and intracellular adhesion molecule 1, and the inflammatory cytokines, interleukin (IL) 1β, IL-6 and IL-8, were downregulated significantly. Mainly genes that changed >10-fold were analyzed in this study, and HOXC8 demonstrated activity in promoting nerve growth. Through the analysis of the mRNA expression of the nerves in the NF1 patients, target molecules contributing to nerve growth during NF1 development were investigated, which aided in improving our understanding of this disease, and may provide a novel direction for nerve repair and regeneration.

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Cell-specific and hypoxia-dependent regulation of human HIF-3α: inhibition of the expression of HIF target genes in vascular cells

Cited by 51 publications

References 55 publications

Hypoxia-inducible factor 3 biology: complexities and emerging themes

Hypoxia-inducible factor 3 biology: complexities and emerging themes

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Microarray-based identification of nerve growth-promoting genes in neurofibromatosis type I

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