HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth.

By K. Covello, J. Kehler, Hongwei Yu, John D. Gordan, A. M. Arsham, Cheng-Jun Hu, P. Labosky, M. C. Simon, B. Keith. Genes & Development, 2006

832 citations recorded by the source corpus.

The division, differentiation, and function of stem cells and multipotent progenitors are influenced by complex signals in the microenvironment, including oxygen availability. Using a genetic "knock-in" strategy, we demonstrate that targeted replacement of the oxygen-regulated transcription factor HIF-1alpha with HIF-2alpha results in expanded expression of HIF-2alpha-specific target genes including Oct-4, a transcription factor essential for maintaining stem cell pluripotency. We show that HIF-2alpha, but not HIF-1alpha, binds to the Oct-4 promoter and induces Oct-4 expression and transcriptional activity, thereby contributing to impaired development in homozygous Hif-2alpha KI/KI embryos, defective hematopoietic stem cell differentiation in embryoid bodies, and large embryonic stem cell (ES)-derived tumors characterized by altered cellular differentiation. Furthermore, loss of HIF-2alpha severely reduces the number of embryonic primordial germ cells, which require Oct-4 expression for survival and/or maintenance. These results identify Oct-4 as a HIF-2alpha-specific target gene and indicate that HIF-2alpha can regulate stem cell function and/or differentiation through activation of Oct-4, which in turn contributes to HIF-2alpha's tumor promoting activity.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/81e865dd18dbf0c0cfa11e63a1c204cbf60fe5c2

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Citations in the corpus

Exploring the role of cancer stem cells in radioresistance (2008, background): “For example, activation of HIF2α (also known as EPAS1 ) may induce the expression of the transcription factor OCT4 (also known as POU5F1 ), which is one of the most important components of stem cell maintenance in different tissue”
Oxygen in stem cell biology: a critical component of the stem cell niche. (2010, background): “The discovery of HIF-2a regulation of Oct4, as well as several downstream targets that maintain stem cell self renewal, has led to a considerable amount of interest in the role of this transcription factor in stem cells (Covello et al., 2006).”
The role of hypoxia-inducible factors in tumorigenesis (2008, positive): “Evidence suggests that primitive hematopoietic and embryonic stem (ES) cells reside in an hypoxic microenvironment, suggesting that low oxygen tensions may play a role in maintaining stem cell fate.90,91 In support of this notion, hypoxia has been shown to maintain human ES (hES) cells in an undiffe”
HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. (2007, background): “…have shared targets, such as vascular endothelial growth factor (VEGF ) and adipose differentiation-related protein (ADRP), they also regulate unique gene targets, with HIF-1α regulating glycolytic enzymes (Hu et al., 2003), and HIF-2α activating the stem cell factor oct4 (Covello et al., 2006).”
The von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer (2008, background): “For example, certain metabolic genes are preferentially activated by HIF1α, whereas erythropoietin and OCT4 (also known as POU5F1 ) are preferentially activated by HIF2&alpha”
Hypoxia-Inducible Factor-1 (HIF-1) (2006, neutral): “However, a recent study using a genetic “knock-in” strategy has shown that targeted replacement of HIF-1 with HIF-2 results in expanded expression of HIF-2 -specific target genes (i.e., Oct-4, a transcription factor essential for maintaining stem cell pluripotency) (Covello et al., 2006).”
Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α (2009, background): “Another tumorigenic property of hypoxia is the activation of specific pathways and transcription factors that control stem cells, such as Notch and Oct4 (Gustafsson Oncogene et al., 2005; Covello et al., 2006).”
Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma (2010, background): “Furthermore, HIF2α , the transcriptional targets of which include POU5F1 (Ref”
HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. (2007, background): “HIF-1a uniquely activates glycolytic enzyme genes, while HIF-2a preferentially activates VEGF, transforming growth factor-a (TGFa), lysyl oxidase, Oct4, and Cyclin D1 (Baba et al., 2003; Covello et al., 2006; Erler et al., 2006; Gunaratnam et al., 2003; Hu et al., 2003; Wang et al., 2005).”
Hypoxia-Inducible Factors Regulate Tumorigenic Capacity of Glioma Stem Cells (2009, neutral): “HIFs Regulate Glioma Stem Cell Tumorigenesis reported to be HIF2a dependent (Oct4 [Covello et al., 2006; Keith and Simon, 2007], glucose transporter type 1 [Glut1] [Keith and Simon, 2007], and SerpinB9 [Holmquist-Mengelbier et al., 2006]) were expressed at significantly higher levels in GSCs as…”
The N-Terminal Transactivation Domain Confers Target Gene Specificity of Hypoxia-inducible Factors HIF-1α and HIF-2α (2007, background): “…et al., 2005; Wang et al., 2005), as well as carbonic hydrase-9 (CA IX) (Grabmaier et al., 2004) and BNIP3 (Raval et al., 2005), whereas HIF-2 exclusively regulates the Pou transcription factor Oct-4, cyclin D1, and transforming growth factor (TGF- ) (Raval et al., 2005; Covello et al., 2006).”
Transcriptional Regulation by Hypoxia Inducible Factors (2013, background): “HIFs regulate several genes that confer stemness properties including the well-known OCT4 (POU5F1), as well as many genes that are involved in epithelial to mesenchymal transition (EMT) during development and utilized by cancer cells in metastasis and invasion such as LOX, MMP1 and TWIST (Covello et”