DEREGULATED C-MYC EXPRESSION OVERRIDES IFN-GAMMA-INDUCED MACROPHAGE GROWTH ARREST

Induction of c-myc gene expression is an essential response to growth promoting agents, including colony-stimulating factor 1 (CSF-1), Down regulation of c-myc expression occurs in response to a variety of nega tive growth regulators in many cell types, However, for many of these systems the causal link between c-myc down regulation and growth arres t remains to be established. Here we show for CSF-l-dependent BAC1.2F5 mouse macrophages that interferon-gamma (IFN gamma) results in a midl ate GI phase decrease of CSF-l-dependent c-myc mRNA and subsequent cel l cycle arrest. Introduction of a deregulated c-myc gene into these ce lls, which prevents the IFN gamma-mediated decrease in c-myc expressio n, overrides the cell cycle arrest and restores CSF-l-dependent growth in the presence of the cytokine, This result contrasts with the macro phage growth arrest induced by cAMP elevation, which also suppresses c -myc expression, but is not overcome by a deregulated c-myc gene, Thes e results show that inhibition of c-myc expression is an essential com ponent in IFN gamma-mediated cell cycle arrest and demonstrates that d istinct mechanisms contribute to IFN gamma- and cAMP-mediated growth a rrest in macrophages.