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CK1 delta restrains lipin-1 induction, lipid droplet formation and cell proliferation under hypoxia by reducing HIF-1 alpha/ARNT complex formation
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2015 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 27, no 6, 1129-1140 p.Article in journal (Refereed) Published
Abstract [en]

Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF-1 alpha, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that CK1 delta phosphorylates HIP-la in its N-terminus and reduces its affinity for its heterodimerization partner ARNT. To investigate the importance of this mechanism for cell proliferation under hypoxia, we visually monitored HIP-1 alpha interactions within the cell nucleus using the in situ proximity ligation assay (PIA) and fluorescence recovery after photobleaching (FRAP). Both methods show that CK1 delta-dependent modification of HIF-1 alpha impairs the formation of a chromatin binding HIF-1 complex. This is confirmed by analyzing expression of lipin-1, a direct target of HIF-1 that mediates hypoxic neutral lipid accumulation. Inhibition of CK1 delta increases lipid droplet formation and proliferation of both cancer and normal cells specifically under hypoxia and in an HIF-1 alpha- and lipin-1-dependent manner. These data reveal a novel role for CK1 delta in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions.

Place, publisher, year, edition, pages
2015. Vol. 27, no 6, 1129-1140 p.
Keyword [en]
Hypoxia, Lipid metabolism, CK1 delta, HIF-1, Lipin1, Lipid droplets
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-253226DOI: 10.1016/j.cellsig.2015.02.017ISI: 000353096700010PubMedID: 25744540OAI: oai:DiVA.org:uu-253226DiVA: diva2:824609
Available from: 2015-06-22 Created: 2015-05-25 Last updated: 2017-12-04Bibliographically approved

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Landegren, Ulf

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Science for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and PathologyMolecular tools
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