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PMID:7519779
| Citation |
Ito, T, Jagus, R and May, WS (1994) Interleukin 3 stimulates protein synthesis by regulating double-stranded RNA-dependent protein kinase. Proc. Natl. Acad. Sci. U.S.A. 91:7455-9 |
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| Abstract |
In a murine interleukin 3 (IL-3)-dependent cell line, IL-3 deprivation resulted in increased autophosphorylation of double-stranded RNA-dependent protein kinase (PKR) that has been reported to inhibit protein synthesis by phosphorylating the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha). Autophosphorylation was characterized by a shift up in mobility of PKR on SDS/PAGE gels from a 60- to a 64-kDa form. In vitro kinase studies comparing the autophosphorylated 64-kDa PKR with the nonphosphorylated 60-kDa PKR confirmed that only the 64-kDa form was active for eIF-2 alpha phosphorylation. PKR activation in vivo was associated with phosphorylation of eIF-2 alpha and inhibition of protein synthesis. Addition of IL-3 to deprived cells elicited a reciprocal response characterized by the rapid dephosphorylation of PKR and eIF-2 alpha, indicating inactivation of PKR. This was rapidly followed by the full recovery of protein synthesis. Furthermore, upon IL-3 addition, a 97-kDa phosphotyrosine-containing protein becomes rapidly and transiently associated with PKR prior to dephosphorylation of PKR and eIF-2 alpha. Genistein, a tyrosine kinase inhibitor, blocks both phosphorylation of the 97-kDa phosphoprotein and protein synthesis after IL-3 addition, suggesting a role for the 97-kDa phosphoprotein in the mechanism of inactivation of PKR and stimulation of protein synthesis. Thus, IL-3 appears to positively regulate protein synthesis by inducing the inactivation of PKR in a growth factor signaling pathway. |
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| Keywords |
Animals; Cells, Cultured; Eukaryotic Initiation Factor-2/metabolism; Gene Expression Regulation, Enzymologic/drug effects; Genistein; Interleukin-3/pharmacology; Isoflavones/pharmacology; Mice; Phosphoproteins/metabolism; Phosphorylation/drug effects; Phosphotyrosine; Protein Biosynthesis/drug effects; Protein-Serine-Threonine Kinases/metabolism; Protein-Tyrosine Kinases/antagonists & inhibitors; Tyrosine/analogs & derivatives; Tyrosine/metabolism; eIF-2 Kinase |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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