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 negative growth regulators in many cell types. However, for many of these systems the causal link between c-myc down regulation and growth arrest remains to be established. Here we show for CSF-1-dependent BAC1.2F5 mouse macrophages that interferon-gamma (IFN gamma) results in a midlate G1 phase decrease of CSF-1-dependent c-myc mRNA and subsequent cell cycle arrest. Introduction of a deregulated c-myc gene into these cells, which prevents the IFN gamma-mediated decrease in c-myc expression, overrides the cell cycle arrest and restores CSF-1-dependent growth in the presence of the cytokine. This result contrasts with the macrophage growth arrest induced by cAMP elevation, which also suppresses c-myc expression, but is not overcome by a deregulated c-myc gene. These results show that inhibition of c-myc expression is an essential component in IFN gamma-mediated cell cycle arrest and demonstrates that distinct mechanisms contribute to IFN gamma- and cAMP-mediated growth arrest in macrophages.
Vairo
G
G
University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Australia.
Vadiveloo
P K
PK
Royston
A K
AK
Rockman
S P
SP
Rock
C O
CO
Jackowski
S
S
Hamilton
J A
JA
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000187:drug effects / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D004247:DNA; D000242:Cyclic AMP