Estrogen receptor-␣ (ER␣) can induce the expression of genes in response to estrogen by binding to estrogen response elements in the promoters of target genes. There is growing evidence that ER␣ can alter patterns of gene expression in response to ligand by regulating the activity of other factors through a direct proteinprotein interaction. To identify other factors that are regulated by ER␣, a yeast two-hybrid screen was performed that identified a novel Cys 2 His 2 zinc finger protein named ZER6. The ZER6 protein contains a Kruppelassociated box domain and six Cys 2 His 2 zinc fingers. Transcripts from the ZER6 gene can have alternate 5 exons and encode either a p71 or p52 isoform. The p52-ZER6 protein interacts strongly with ER␣ in the presence of 17␤-estradiol, whereas the p71-ZER6 isoform has a HUB-1 amino-terminal domain that inhibits the interaction with ER␣. A consensus ZER6 binding element was defined using PCR-assisted binding site selection. In COS-1 cells, both the p52 and p71 isoforms can activate transcription through the ZER6 binding element; however, in the presence of ER␣, transactivation by the p52 isoform is specifically repressed. Overexpression of the p52 isoform was able to abrogate activation by p71-ZER6. Expression of ZER6 was largely restricted to the mammary gland with a lower level of expression in the kidney. We conclude that ZER6 is a novel zinc finger transcription factor in which regulation of transcription in hormone-responsive cells can be controlled by the relative level of expression of two distinct isoforms. Two human estrogen receptors (ERs)1 have been identified: ER␣ and ER␤ (1-4). These nuclear receptors are members of the steroid-thyroid-retinoic acid superfamily of transcription factors (5). In the classic model of transactivation by the receptor, ligand-activated ER␣ forms a homodimer, which is able to bind specific DNA regulatory sequences in the promoters of ER␣ target genes called estrogen response elements (6). This mechanism of transactivation by ER␣ induces the expression of a set of target genes in hormone-responsive tissues and tumors. Several ER␣ target genes have been described in hormoneresponsive breast tumors including progesterone receptor (7), pS2(8), transforming growth factor-␣ (9), cathepsin D (10), HSP27(11), and GREB1(12). The promoters of these genes are directly activated by ER␣, and induction of target gene expression is dependent upon the ability of ER␣ to bind to DNA.Over the past several years, data have been accumulating demonstrating that ER␣ can alter the expression of genes independent of direct DNA binding. One mechanism that has been proposed is through the ability of ER␣ to regulate the activity of other nuclear transcription factors by mechanisms involving direct protein-protein interactions. In many cases the interactions between ER␣ and other nuclear factors have been shown to be ligand-dependent. One example of this alternate mechanism of gene regulation is the effect of ER␣ on expression of genes regulated by AP1(13). ER␣ and ER␤ ha...

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