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
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Mentions: In agreement with our previously published data , the siRNA against HIF-1α was effective in reducing the expression of both HIF-1α and lipin-1 under hypoxia (Fig. 7a, upper panel), while the siRNA against lipin-1 decreased the expression of lipin-1 under all conditions (Fig. 7b, upper panel). As expected, knocking down HIF-1α did not affect cell proliferation under normoxia, irrespective of D4476 treatment. However, hypoxic stimulation of proliferation and its further enhancement by D4477 were both greatly abolished when HIF-1α expression was silenced (Fig. 7a, bottom panel). Depletion of lipin-1 did not significantly alter cellular proliferation under normoxia. In contrast, suppression of lipin-1 expression significantly decreased hypoxia-stimulated cellular proliferation, and it almost completely neutralized the positive effect of CK1δ inhibition (Fig. 7b, lower panel). These data lead to the conclusion that increased proliferation of cells under hypoxia requires HIF-1 and also, surprisingly, a lipin-1-mediated function such as, possibly, up-regulation of lipid droplet formation. CK1δ restricts this phenomenon and can limit cellular proliferation under hypoxia by modifying HIF-1α and impairing its association with ARNT and DNA (Fig. 7c).
Affiliation: Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece.