Developmentally specific effects of the DNA cross-linking agent mitomycin C on phosphoenolpyruvate carboxykinase gene expression in vivo: correlation with changes in chromatin structure within the promoter region of the gene.
Previous studies in our laboratory have demonstrated that genotoxic chemical carcinogens have strong preferential effects on expression of certain inducible genes at nonovertly toxic doses in vivo. The effects of the DNA cross-linking agent and chemotherapy drug, mitomycin C (MMC), on expression of the developmental and hormone-regulated gene, phosphoenolpyruvate carboxykinase (PEPCK), were examined in chick embryo liver in vivo as a function of development and were compared with changes in the chromatin structure of the PEPCK gene promoter. The liver PEPCK gene was fully hormone inducible as early as 8 days of embryonic development but was refractory to MMC until after day 10. This onset of responsiveness to MMC was correlated with qualitative changes in the pattern of DNase I hypersensitive sites (DHS) within the PEPCK promoter. There was also a gradual decrease and then a complete loss of both hormone inducibility and MMC responsiveness between 14 and 17 days of development that was correlated with a quantitative change in the overall DNase sensitivity of the liver PEPCK gene promoter over this period. These results suggest that carcinogen sensitivity of the PEPCK gene is related to its ability to respond to its normal induction signals and that chromatin structure may play a central role in these effects.
Caron
R M
RM
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755-3835, USA.
Hamilton
J W
JW
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002642:Chick Embryo; D002843:Chromatin / Q000737:chemistry*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D016685:Mitomycin / Q000494:pharmacology*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics
D018906:Antineoplastic Agents, Alkylating; D002843:Chromatin; D012333:RNA, Messenger; D016685:Mitomycin; D019764:Phosphoenolpyruvate Carboxykinase (ATP)