Chelation of zinc amplifies induction of growth hormone mRNA levels in cultured rat pituitary tumor cells.
Zinc is thought to be an integral part of nuclear receptor proteins, stabilizing them in a conformation required for binding to target genes. However, we have recently shown that restriction of zinc availability with a chelator (diethylenetriaminepenta-acetic acid, DTPA) enhances, rather than inhibits, the ability of thyroid hormone to induce growth hormone mRNA expression in GH3 rat pituitary tumor cells. In this report, we have extended these observations by showing that a prolonged (48 h) exposure to DTPA is required to see these effects. The induction by DTPA can be reversed by subsequent addition of zinc, but again, this reversal is slow. A second chelator, EDTA, can also induce growth hormone gene expression in the presence of thyroid hormone, though it is less potent than DTPA. Other agents which act via the nuclear receptor pathway, all-trans and 9-cis retinoic acid, also induce expression of growth hormone mRNA. Addition of DTPA amplifies these effects in a zinc-dependent manner. Thus chelation of zinc potentiates the action of ligands acting via nuclear receptors on growth hormone gene expression. The delayed nature of the response suggests an indirect effect.
Sciaudone
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Department of Nutritional Sciences, University of Connecticut, Storrs 06269-4017, USA.
Chattopadhyay
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Freake
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D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015152:Blotting, Northern; D002614:Chelating Agents / Q000627:therapeutic use*; D004347:Drug Interactions; D004492:Edetic Acid / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D013006:Growth Hormone / Q000187:drug effects* / Q000235:genetics*; D004369:Pentetic Acid / Q000627:therapeutic use; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D014212:Tretinoin / Q000627:therapeutic use; D014284:Triiodothyronine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002614:Chelating Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014284:Triiodothyronine; D014212:Tretinoin; D004369:Pentetic Acid; D013006:Growth Hormone; D004492:Edetic Acid; D015032:Zinc