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.
['Kourti|Maria|M|', 'Ikonomou|Georgia|G|', 'Giakoumakis|Nikolaos-Nikiforos|NN|', 'Rapsomaniki|Maria Anna|MA|', 'Landegren|Ulf|U|', 'Siniossoglou|Symeon|S|', 'Lygerou|Zoi|Z|', 'Simos|George|G|', 'Mylonis|Ilias|I|']
D048148:Casein Kinase Idelta 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 D066292:Lipid Droplets D050356:Lipid Metabolism D010711:Phosphatidate Phosphatase D010766:Phosphorylation D034622:RNA Interference D034741:RNA, Small Interfering
CK1δ Lipid droplets Hypoxia HIF-1 Lipid metabolism Lipin1