OPPOSITE REGULATION OF GENE-TRANSCRIPTION AND CELL-PROLIFERATION BY C-MYC AND MAX

c-Myc and Max are nuclear phosphoproteins capable of forming DNA-binding, homo- and heteropolymeric complexes in vitro and in vivo. Using a transient cotransfection assay involving c-Myc and Max expression vectors and a reporter gene plasmid containing the Myc/Max binding site, we find that Max represses transcription, whereas a significant stimulation is obtained when Max is coexpressed with c-Myc. Analysis of specific mutants indicates that transcriptional activation requires both the c-Myc and the Max dimerization and DNA-binding domains, as well as the c-Myc transactivation function; transcriptional repression by Max requires both DNA binding and dimerization. Analogously, in stably transfected human B-lymphoblastoid cell lines, overexpressed c-Myc and Max synergize to cause malignant transformation, whereas overexpression of Max alone leads to growth inhibition. These results indicate that the c-Myc and Max are transcriptional regulators with the ability to oppositely regulate target-gene expression and cell proliferation, most likely as the result of the opposite effects of heterodimeric c-Myc-Max (positive) versus homodimeric Max (negative) complexes.