A PAIR OF ADJACENT GLUCOCORTICOID RESPONSE ELEMENTS REGULATE EXPRESSION OF 2 MOUSE METALLOTHIONEIN GENES

Synthesis of mouse metallothionein (MT)-I and MT-II is transcriptional ly induced by the synthetic glucocorticoid, dexamethasone (DEX) or bot h in vivo as well as in numerous cell lines, However, the location(s) of a glucocorticoid response element (GRE) has not been described, The observation that a marked MT-I gene, as well as heterologous genes, w hen placed in the context of 17 kb of flanking sequence from the MT lo cus, are inducible by DEX and lipopolysaccharide in transgenic mice re newed the search for the GRE, Analysis of a series of deletion constru cts from this 17-kb region in cultured cells identified a single 455-b p region that conferred DEX induction on a reporter gene, This 455-bp region contains two GREs that bind to the glucocorticoid receptor as a ssessed by gel mobility shift. Deletion of this fragment from the 17-k b flanking region eliminates the DEX responsiveness of reporter genes, The two GREs, which are located approximate to 1 kb upstream of the M T-II gene and approximate to 7 kb upstream of the MT-I gene, are neces sary for induction of both genes and can function independently of ele ments within the proximal promoter region of either gene.