CK1δ restrains lipin-1 induction, lipid droplet formation and cell proliferation under hypoxia by reducing HIF-1α/ARNT complex formation

Cellular Signalling
Maria KourtiIlias Mylonis

Abstract

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.

References

Aug 12, 2010·Journal of Cell Science·Alkmini KalousiGeorge Simos
Aug 6, 2011·Cell·Timothy R PetersonDavid M Sabatini
Mar 9, 2012·Trends in Pharmacological Sciences·Gregg L Semenza
Apr 3, 2012·Journal of Cell Science·Ilias MylonisGeorge Simos
Mar 6, 2013·Biochimica Et Biophysica Acta·Aggeliki LyberopoulouEleni Georgatsou
Nov 2, 2014·Nature Reviews. Drug Discovery·Holger K EltzschigSean P Colgan

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Citations

Jul 8, 2016·International Journal of Molecular Sciences·Gagan Deep, Isabel R Schlaepfer
Sep 3, 2016·International Journal of Molecular Sciences·Shiro Koizume, Yohei Miyagi
Oct 1, 2016·Journal of Cell Science·Evanthia PangouPanagiotis Liakos
May 10, 2019·Expert Opinion on Drug Discovery·Najah AlbadariWei Li
Mar 31, 2019·Molecular & Cellular Proteomics : MCP·Georgia ChachamiGeorge Simos
May 19, 2017·Scientific Reports·Huanxian CuiJie Wen
Dec 12, 2018·Cellular and Molecular Life Sciences : CMLS·Angeliki KaragiotaIlias Mylonis
Mar 6, 2019·Cells·Ilias MylonisEfrosyni Paraskeva
Jan 28, 2021·Cancers·Ilias MylonisGeorge Simos
Jun 1, 2019·Molecular & Cellular Proteomics : MCP·Georgia ChachamiGeorge Simos
Mar 25, 2017·Experimental Cell Research·Gregg L Semenza
Feb 19, 2019·Archives of Biochemistry and Biophysics·Angeliki KaragiotaGeorgia Chachami
Jun 3, 2021·International Journal of Molecular Sciences·Vittoria InfantinoVito Iacobazzi

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Methods Mentioned

BETA
FCS
immunoprecipitation
proximity
Fluorescence
proximity ligation assay
fluorescence recovery after photobleaching

Software Mentioned

ImageJ
Alliance
GraphPad Prism
easyFRAP
ITCN

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