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Association of 2',5'-Oligoadenylate Synthetase with the Prolactin (PRL) Receptor: Alteration in PRL-Inducible Stat1 (Signal Transducer and Activator of Transcription 1) Signaling to the IRF-1 (Interferon-Regulatory Factor 1) Promoter

Departments of Medicine (K.M.M., L-y.Y.-L.), Molecular and Cellular Biology (M.L.B., L.-y.Y.-L), and Immunology (P.L., L.-y.Y.-L.) Baylor College of Medicine Houston, Texas 77030-3411
Department of Molecular Genetics (J.C.) Weizmann Institute of Sciences Rehovot, Israel 76100

The PRL receptor (PRL-R) signals through the Janus tyrosine kinases (JAK) and other non-JAK tyrosine kinases, some of which are preassociated with the PRL-R. To clone PRL-R interacting proteins, the intracellular domain (ICD) of the long form of the PRL-R was used in a yeast two-hybrid screen of a human B cell cDNA library. One PRL-R interacting protein was identified as the 42-kDa form of the enzyme 2',5'-oligoadenylate synthetase (OAS). The in vivo interactions in yeast were further confirmed by an in vitro interaction assay and by coimmunoprecipitation in transfected mammalian cells. Functionally, OAS reduced the basal activity of two types of promoters in transiently transfected COS-1 cells. In the presence of PRL, OAS inhibited PRL induction of the immediate early IRF-1 (interferon-regulatory factor 1) promoter, but not PRL induction of the differentiation-specific ß-casein promoter, suggesting that OAS exerts specific effects on immediate early gene promoters. The inhibitory effects of OAS were accompanied by a reduction in PRL-inducible Stat1 (signal transducer and activator of transcription 1) DNA binding activity at the IRF-1 GAS (interferon--activated sequence) element. These results demonstrate a novel interaction of OAS with the PRL-R and suggest a role for OAS in modulating Stat1-mediated signaling to an immediate early gene promoter. Although previously characterized as a regulator of ribonuclease (RNase) L antiviral responses, OAS may have additional effects on cytokine receptor signal transduction pathways.

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