TRANSCRIPTIONAL INDUCTION OF THE PML GROWTH SUPPRESSOR GENE BY INTERFERONS IS MEDIATED THROUGH AN ISRE AND A GAS ELEMENT

PML is a nuclear matrix protein with growth suppressing properties, wh ose expression is deregulated during oncogenesis. Moreover, in the t(1 5;17) translocation of acute promyelocytic leukaemia (APL), PML fusion to the retinoic acid receptor alpha (RAR alpha) is the likely molecul ar basis of leukaemogenesis. Here we show that interferons (IFNs) alph a, beta, and gamma upregulate PML mRNA expression. Analysis of 5' geno mic sequences of the PML gene revealed an IFN-alpha/-beta stimulated r esponse element (ISRE) and an IFN-gamma activation site (GAS) in the u ntranslated first exon. Binding of TFN signal transducers and activato rs of transcription (STATs) was demonstrated to be weak for the PML GA S, but strong for the PML ISRE which also seemed to contribute substan tially to the IFN-gamma response. Thus, PML is a primary target gene o f IFNs and would appear as a suitable candidate for mediating some of their antiproliferative effects. Abnormalities of PML structure, local isation or expression in human malignancy, constitute examples of how an IFN target gene may be altered in oncogenesis.