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      Role of HIF1 α Regulatory Factors in Stem Cells

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          Abstract

          Hypoxia-inducible factor 1 (HIF1) is a master transcription factor that induces the transcription of genes involved in the metabolism and behavior of stem cells. HIF1-mediated adaptation to hypoxia is required to maintain the pluripotency and survival of stem cells under hypoxic conditions. HIF1 activity is well known to be tightly controlled by the alpha subunit of HIF1 (HIF1 α). Understanding the regulatory mechanisms that control HIF1 activity in stem cells will provide novel insights into stem cell biology under hypoxia. Recent research has unraveled the mechanistic details of HIF1 α regulating processes, suggesting new strategies for regulating stem cells. This review summarizes recent experimental studies on the role of several regulatory factors (including calcium, 2-oxoglutarate-dependent dioxygenase, microtubule network, importin, and coactivators) in regulating HIF1 α activity in stem cells.

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          Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.

          Weibo Luo, Hongxia Hu, Ryan Chang … (2011)
          The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by hypoxia-inducible factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.

            James Brugarolas, Kui Lei, Rebecca Hurley … (2004)
            Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.
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              FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.

              P Mahon, K Hirota, G. L. Semenza (2001)
              Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. O(2)-dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1alpha subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1alpha transactivation domains is also O(2) regulated by a previously undefined mechanism. Here, we report the identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1alpha and inhibits its transactivation function. In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF-1alpha transactivation function by recruiting histone deacetylases. Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation of HIF-1alpha protein stabilization and transcriptional activation in response to changes in cellular O(2) concentration.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Stem Cells
                Journal ID (iso-abbrev): Int J Stem Cells
                Journal ID (publisher-id): IJSC
                Title: International Journal of Stem Cells
                Publisher: Korean Society for Stem Cell Research
                ISSN (Print): 2005-3606
                ISSN (Electronic): 2005-5447
                Publication date Collection: 2019
                Publication date (Electronic): 28 February 2019
                Volume: 12
                Issue: 1
                Pages: 8-20
                Affiliations
                Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, Korea
                Author notes
                Correspondence to: Ho Jae Han, Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea, Tel: +82-2-880-1261, Fax: +82-2-880-2732, E-mail: hjhan@ 123456snu.ac.kr
                Article
                Publisher ID: ijsc-12-008
                DOI: 10.15283/ijsc18109
                PMC ID: 6457711
                PubMed ID: 30836734
                SO-VID: dc49866d-5058-40dd-b0c1-68a5e1b63dca
                Copyright © Copyright © 2019 by the Korean Society for Stem Cell Research
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 10 November 2018
                Date revision received : 17 December 2018
                Date accepted : 18 December 2018
                Categories
                Subject: Review Article

                Keywords: stem cells,hypoxia-inducible factor 1 alpha (hif1α),calcium,2-oxoglutrate-dependent dioxygenase (2ogdd),microtubule,importin
                Data availability:
                Keywords: stem cells, hypoxia-inducible factor 1 alpha (hif1α), calcium, 2-oxoglutrate-dependent dioxygenase (2ogdd), microtubule, importin

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