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

Cell Signal. 2015 Jun;27(6):1129-40. doi: 10.1016/j.cellsig.2015.02.017. Epub 2015 Mar 3.


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.

Keywords: CK1δ; HIF-1; Hypoxia; Lipid droplets; Lipid metabolism; Lipin1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Casein Kinase Idelta / metabolism*
  • Cell Hypoxia
  • Cell Line
  • Cell Proliferation
  • Fluorescence Recovery After Photobleaching
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Lipid Droplets / physiology*
  • Lipid Metabolism
  • Phosphatidate Phosphatase / metabolism*
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / metabolism


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Casein Kinase Idelta
  • LPIN1 protein, human
  • Phosphatidate Phosphatase