Abstract
PKR and PKR-like Endoplasmic Reticulum Kinase Induce the Proteasome-dependent Degradation of Cyclin D1 via a Mechanism Requiring Eukaryotic Initiation Factor 2α Phosphorylation
Highlights
Transcription of the cyclin D1 gene is increased upon many different types of stimuli, including insulin-like growth factor-1 (IGF-1 [7]) and IGF-II [8], amino acids [9], androgens [10], and retinoic acid [11], depending on the cell type
Four eIF2␣ kinases have been identified to date that are each activated under different conditions but which all act to inhibit global protein synthesis, including the protein kinase activated by double-stranded RNA (PKR), which reacts to virus infection (Kaufman, 2000) [24], PKR-like ER kinase (PERK) activated by endoplasmic endoplasmic reticulum (ER) stress [25], hemeregulated inhibitor activated by heme deficiency (HRI) [26], and general control non-derepressible-2 (GCN2), which responds to amino acid starvation [27]
To determine whether the observed effect on cyclin D1 was due to decreased translation as previously proposed, we examined translation of cyclin D1 mRNA using polysome profiles on HT1080 cells treated with either thapsigargin or Sal003
Summary
Transcription of the cyclin D1 gene is increased upon many different types of stimuli, including insulin-like growth factor-1 (IGF-1 [7]) and IGF-II [8], amino acids [9], androgens [10], and retinoic acid [11], depending on the cell type. Treatment with thapsigargin induced inhibition of global translation initiation in eIF2␣ S/S, but not A/A cells (compare panels ii and iv), but cyclin D1 mRNA remained associated with the polysome fractions (Fig. 2C, panel a).
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