CK1δ restrains lipin-1 induction, lipid droplet formation and cell proliferation under hypoxia by reducing HIF-1α/ARNT complex formation.
Bottom Line: We have previously shown that CK1δ phosphorylates HIF-1α in its N-terminus and reduces its affinity for its heterodimerization partner ARNT.This is confirmed by analyzing expression of lipin-1, a direct target of HIF-1 that mediates hypoxic neutral lipid accumulation.These data reveal a novel role for CK1δ in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions.
Affiliation: Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece.Show MeSH
Related in: MedlinePlus
Mentions: To investigate the effect of these changes on triglyceride metabolism we examined the formation of lipid droplets in HeLa cells incubated with D4476 for 24 h under normoxic or hypoxic conditions. Treatment with D4476 significantly increased lipid droplet formation under hypoxia (Fig. 5a, left panel and Supplementary Fig. 3a), indicating increased triglyceride production via up-regulation of the HIF-1 and lipin-1. To see if the changes triggered by CK1δ inhibition would affect cellular adaptation to hypoxia, we measured the proliferation of HeLa under the same conditions. Inhibition of CK1δ did not significantly affect cellular growth rate under normoxic conditions. However, under hypoxia, D4476 caused a small but statistically significant increase in cell proliferation, in agreement with its positive effect on HIF-1 activity (Fig. 5a, right panel). We then tested the effects of CK1δ inhibition on lipid droplet accumulation and cell proliferation in normal, non-cancer cells by using primary, non-transformed human bronchial smooth muscle (hBSM) cells. The results were similar as with HeLa cells (Fig. 5b and Supplementary Fig. 3b), suggesting that the CK1δ-HIF-1α-lipin-1 regulatory axis operates irrespective of the cellular transformation status.
Affiliation: Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece.