GRANULOCYTE MACROPHAGE-COLONY-STIMULATING FACTOR-DEPENDENT REPLICATION OF POLYOMA-VIRUS REPLICON IN HEMATOPOIETIC-CELLS - ANALYSES OF RECEPTOR SIGNALS FOR REPLICATION AND TRANSCRIPTION

Granulocyte macrophage colony stimulating factor (GM-CSF) stimulates p roliferation of various hemato poietic cells. Using cytoplasmic deleti on mutants of the human GM-CSF receptor (hGMR) beta subunit and tyrosi ne kinase inhibitors, we previously showed that distinct signaling pat hways of hGMR are involved in the induction of c-fos/c-jun mRNAs and o f c-myc mRNA/cell proliferation. We used polyoma virus (Py) replicon t o analyze the initiation of DNA replication induced by hGM-CSF in mous e BA/F3 pro-B cells expressing hGMR. hGM-CSF efficiently stimulated Py replication in the presence of Py enhancer and Py large T antigen sup plied in trans. Analyses of Py enhancer mutants revealed that hGM-CSF promoted Py replication and activated transcription of the Py early pr omoter through the PEA3/PEBP5 region of Py enhancer. The membrane prox imal region of hGMR beta subunit is required for activation of PEA3/PE BP5-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 t he PEA3/PEBP5-dependent transcription of Py early promoter. These resu lts indicate that distinct signaling pathways of hGMR are required to activate PEA3/PEBP5-dependent replication and transcription although t he same enhancer is required for both activities.