title: Germ line c-myc is not down-regulated by loss or exclusion of activating factors in myc-induced macrophage tumors.
abstract: As in tumors with c-myc chromosomal translocations, c-myc retrovirus-induced monocyte tumors constitutively express an activated form of c-myc (the proviral gene), whereas the normal endogenous c-myc genes are transcriptionally silent. Treatment of these retrovirus-induced tumor cells with a number of bioactive chemicals and growth factors that are known to induce c-myc expression in cells of the monocyte lineage failed to induce the endogenous c-myc gene. In contrast, the same treatments induced the c-fos gene in both tumors and a control macrophage line. To investigate c-myc suppression further, a normal copy of the human c-myc gene was introduced into tumor and control cell lines by using a retrovirus with self-inactivating long terminal repeats. This transduced normal gene was expressed at equivalent levels in all cells, regardless of the state of endogenous c-myc gene expression, and was strongly induced by agents that induce the normal gene in the control cells. These results indicate that the signal transduction pathways that normally activate the c-myc gene are functional in myc-induced tumor cells and suggest that endogenous c-myc is actively suppressed. An examination of the c-myc locus itself showed that the lack of transcriptional activity correlated with the absence of several prominent DNase I-hypersensitive sites in the 5'-flanking region of the gene but without loss of general DNase sensitivity. Furthermore, analysis of 22 methylation-sensitive restriction enzyme sites in the 5'-flanking region, first exon, and first intron indicated that the silent c-myc genes remained in the same unmethylated state as did actively expressed genes. Thus, c-myc suppression does not appear to result from the most frequently described mechanisms of gene inactivation.
authors: Lewis Thomas Laboratory, Department of Biology, Princeton University, New Jersey 08544-1014.
authors: S E
authors: SE
authors: Mango
authors: G D
authors: GD
authors: Schuler
authors: M E
authors: ME
authors: Steele
authors: M D
authors: MD
authors: Cole
mesh_terms: D000818:Animals; D001483:Base Sequence; D003994:Bucladesine / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002843:Chromatin / Q000648:ultrastructure; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D003850:Deoxyribonuclease I; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000473:pathology*; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D009857:Oncogenes; D012313:RNA / Q000096:biosynthesis; D012689:Sequence Homology, Nucleic Acid; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D003115:Colony-Stimulating Factors; D012313:RNA; D003994:Bucladesine; D004247:DNA; D003850:Deoxyribonuclease I; D013755:Tetradecanoylphorbol Acetate