CK1δ restrains lipin-1 induction, lipid droplet formation and cell proliferation under hypoxia by reducing HIF-1α/ARNT complex formation.
Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF-1α, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that CK1δ phosphorylates HIF-1α 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 HIF-1α interactions within the cell nucleus using the in situ proximity ligation assay (PLA) and fluorescence recovery after photobleaching (FRAP). Both methods show that CK1δ-dependent modification of HIF-1α 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 CK1δ increases lipid droplet formation and proliferation of both cancer and normal cells specifically under hypoxia and in an HIF-1α- and lipin-1-dependent manner. These data reveal a novel role for CK1δ in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions.
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece.
Maria
M
Kourti
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece; Department of Immunology, Genetics and Pathology, SciLifeLab, Uppsala University, Uppsala, Sweden.
Georgia
G
Ikonomou
Laboratory of Biology, School of Medicine, University of Patras, Rio, Patras, Greece.
Nikolaos-Nikiforos
NN
Giakoumakis
Laboratory of Biology, School of Medicine, University of Patras, Rio, Patras, Greece.
Maria Anna
MA
Rapsomaniki
Department of Immunology, Genetics and Pathology, SciLifeLab, Uppsala University, Uppsala, Sweden.
Ulf
U
Landegren
Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
Symeon
S
Siniossoglou
Laboratory of Biology, School of Medicine, University of Patras, Rio, Patras, Greece.
Zoi
Z
Lygerou
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece. Electronic address: simos@med.uth.gr.
George
G
Simos
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece. Electronic address: mylonis@med.uth.gr.
Ilias
I
Mylonis
D048148:Casein Kinase Idelta / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D036681:Fluorescence Recovery After Photobleaching; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066292:Lipid Droplets / Q000502:physiology*; D050356:Lipid Metabolism; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D048148:Casein Kinase Idelta; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase
CK1δ; HIF-1; Hypoxia; Lipid droplets; Lipid metabolism; Lipin1