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Granulocyte Macrophage-Colony Stimulating Factor-dependent Replication of Polyoma Virus Replicon in Hematopoietic Cells

Granulocyte macrophage-colony stimulating factor (GM-CSF) stimulates proliferation of various hematopoietic cells. Using cytoplasmic deletion mutants of the human GM-CSF receptor (hGMR) β subunit and tyrosine kinase inhibitors, we previously showed that distinct signaling pathways of hGMR are involved in the induction of c- fos/c- jun mRNAs and of c- myc mRNA/cell proliferation. We used polyoma virus (Py) replicon to analyze the initiation of DNA replication induced by hGM-CSF in mouse BA/F3 pro-B cells expressing hGMR. hGM-CSF efficiently stimulated Py replication in the presence of Py enhancer and Py large T antigen supplied in trans. Analyses of Py enhancer mutants revealed that hGM-CSF promoted Py replication and activated transcription of the Py early promoter through the PEA3/PEBP5 region of Py enhancer. The membrane proximal region of hGMR β subunit is required for activation of PEA3/PEBP5-dependent replication which is also required for activation of DNA synthesis in the host cells. In contrast, a more distal region which is essential for activation of c- fos and c- jun genes is required for the PEA3/PEBP5-dependent transcription of Py early promoter. These results indicate that distinct signaling pathways of hGMR are required to activate PEA3/PEBP5-dependent replication and transcription although the same enhancer is required for both activities.