The biological roles of estrogen-responsive finger protein (efp) in vivo were evaluated in mice carrying a loss-of-function mutation in efp by gene-targeted mutagenesis. Although efp homozygous mice were viable and fertile in both sexes, the uterus that expressed abundant estrogen receptor ␣ exhibited significant underdevelopment. When the ovariectomized homozygotes were subjected to 17-estradiol treatment, they showed remarkably attenuated responses to estrogen, as exemplified by decreased interstitial water imbibition and retarded endometrial cell increase, at least, attributable to the lower ratio of G1 to S-phase progression in epithelial cells. These results suggest that efp is essential for the normal estrogen-induced cell proliferation and uterine swelling as one of the direct targets of estrogen receptor ␣.
It is known that estrogen is not only essential in the reproductive system as a sex steroid hormone but also effective to protect postmenopausal women from osteoporosis, coronary heart disease, and Alzheimer disease (1, 2). Estrogen receptors (ERs) such as ER␣ and ER (3-6) act as estrogen-dependent transcription factors by binding to specific estrogen-responsive elements (ERE) in the enhancer region of target genes and regulating their transcription directly (7,8). The liganddependent activation of ERs is accompanied by an induction of binding of coactivator proteins that facilitate functional interaction of the receptors with the general transcription machinery (9-11). Although it is generally believed that estrogen could exert its action on target organs by regulating target gene products, relatively few target genes with consensus ERE are known so far, including vitellogenin (12), ovalbumin (13), lactoferrin (14), prolactin (15), progesterone receptor (16), cathepsin D1 (17), and pS2 (18). Just how these genes actually mediate which part of estrogen action in vivo has been quite difficult to evaluate. Besides, molecular mechanisms of estrogen action are more complicated by additional cascade via factors such as AP-1 (19). We have therefore been trying to obtain more downstream target genes of ER␣ by using a method named genomic bindingsite cloning in which genomic ERE-containing DNA fragments are isolated by binding with the DNA binding domain of the recombinant ER␣ protein (20)(21)(22).We have thus cloned from a human cDNA library several estrogen-regulated genes, one of which was designated the estrogen-responsive finger protein (efp) gene (23-25). Both human and mouse efp cDNAs possess a palindromic ERE in 3Ј noncoding region, and the proteins have a RING finger domain at the N terminus that might be involved in the protein-protein interaction. These proteins also have a pair of zinc fingers and a coiled-coil region in the 3Ј-terminal side of the RING finger domain, a structure resembling promyelocytic leukemia (26)(27)(28)(29) and Midline 1 (30). Incidentally, BRCA1 (31), which is the suppressor of a type of familial mammary carcinoma, also has the RING finger, but not the zinc fingers. The m...
