REGULATION OF IL-3 RECEPTOR EXPRESSION - EVIDENCE FOR A POSTTRANSCRIPTIONAL MECHANISM THAT DOMINANTLY SUPPRESSES THE EXPRESSION OF BETA-SUBUNITS

The IL-3 receptor (IL-3R) is composed of alpha and beta subunits. Two homologous beta subunits of IL-3R are present in the mouse: AIC2A is t he IL-3 specific beta subunit, and AIC2B is the common beta subunit sh ared by IL-3, IL-5 and granulocyte macrophage colony stimulating (GM-C SF) factor receptors. Both beta subunits form functionally indistingui shable high-affinity IL-3Rs with the same IL-3R specific alpha subunit (IL-3R alpha or SUT-1). Cell surface expression of the alpha and beta subunits of IL-3R was found to be diminished in an IL-3 non-responsiv e variant (MC/9.IL-4) derived from an IL-3-dependent mast cell line, M C/9. This IL-3R-defective phenotype was dominant based on cell fusion experiments. Moreover, regulatory mechanisms of the alpha and beta sub units are distinct since cell hybrids between MC/9.IL-4 and a CTLL-2 t ransfectant (CTLL/AS) expressing AIC2A and IL-3R alpha showed a signif icantly reduced expression of the AIC2A mRNA, while the IL-3R alpha ex pression was unchanged. Since transcription of both AIC2A and IL-3R al pha cDNAs in the CTLL/AS was driven by an artificial promoter, SR alph a, and nuclear run-off assays showed similar transcriptional rates of the AIC2A gene in both CTLL/AS and the cell hybrids between MC/9.IL-4 and CTLL/AS, the dominant suppression of the beta subunits is post-tra nscriptional and sequence-specific. A target sequence of the negative regulator must be present within 2756 bases of AIC2A mRNA, which is tr anscribed from the transfected cDNA in CTLL/AS cells. Similar dominant suppression of the beta subunit expression was also found in a B cell line WEH1231. As the negative regulator suppresses expression of the beta subunits of IL-3, IL-5 and GM-CSF receptors, it has the potential to eliminate all three high-affinity receptors simultaneously.