title: Post-translational cooperativity of ornithine decarboxylase induction by estrogens and peptide growth factors in human breast cancer cells.
abstract: Mutual interactions between 17 beta-estradiol (E2) and insulin or insulin-like growth factor-I (IGF-1) in the regulation of ornithine decarboxylase (ODC) expression were examined in estrogen-responsive MCF-7 human breast cancer cells. Whereas E2 only retarded the rapid decay of ODC activity observed upon mitogen withdrawal, both insulin and IGF-1 led to a rapid (< 4 h), net increase in ODC activity that was mediated, at least in part, through their cognate receptors. E2 synergistically potentiated the induction of ODC by IGF-1, resulting in a 170-fold elevation of enzyme activity after 48 h, as compared with 23- and 70-fold increases caused by E2 and IGF-1 alone, respectively. Cooperativity was more pronounced at suboptimal peptide concentrations due to a decrease in the half-maximal concentration of insulin or IGF-1 required for ODC induction. Phorbol-12-myristate-13-acetate (PMA) also strongly induced ODC activity in a transient manner, and additively to the effect of IGF-1. IGF-1 and PMA additively increased ODC mRNA level, whereas E2 alone had no effect on ODC mRNA abundance. IGF-1 increased the half-life of ODC activity by 60%, whereas E2 or PMA alone had no significant effect on enzyme stability. On the other hand, the simultaneous addition of IGF-1 and either E2 or PMA cooperatively reduced ODC turnover, resulting in 3.5- and 2-fold increases, respectively, in the half-life of ODC activity. Thus, ODC expression in breast cancer cells is primarily regulated by tyrosine kinase- and protein kinase C-dependent pathways, whereas estrogens increase ODC activity through a novel type of synergistic interaction with growth factors that results in a decreased rate of enzyme turnover.
authors: Laboratory of Molecular Endocrinology, Laval University Medical Research Centre, Ste. Foy, Quebec, Canada.
authors: M
authors: M
authors: Huber
authors: R
authors: R
authors: Poulin
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004357:Drug Synergism; D004790:Enzyme Induction; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D004967:Estrogens; D007328:Insulin; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate