The steroid hormone 17␤-estradiol (E 2 ) is a key regulator of growth, differentiation, and function in a wide array of target tissues, including the male and female reproductive tracts, mammary gland, and skeletal and cardiovascular systems. The predominant biological effects of E 2 are mediated through two distinct intracellular receptors, ER␣ 1 and ER␤, each encoded by unique genes (1) but possessing the hallmark modular structure of functional domains characteristic of the steroid/thyroid hormone superfamily of nuclear receptors (introduced in the Minireview Prologue (54)). Certain functional domains of the ER␣ and ER␤ exhibit a high degree of homology, namely the DNA-and ligand-binding domains, at 97 and 60%, respectively, whereas considerable divergence is apparent in the N terminus (18% homology). Hence, ER␣ and ER␤ interact with identical DNA response elements and exhibit a similar binding affinity profile for an array of endogenous, synthetic, and naturally occurring estrogens when assayed in vitro (2). In vitro studies also suggest the two receptors may play redundant roles in estrogen signaling; however, tissue localization studies have revealed distinct expression patterns for each receptor that suggest otherwise. Whereas ER␣ is the predominant subtype expressed in the breast, uterus, cervix, vagina, and several additional target organs, ER␤ exhibits a more limited expression pattern and is primarily detected in the ovary, prostate, testis, spleen, lung, hypothalamus, and thymus (3). Regional expression differences of the two receptors have been identified in the brain (4). Further evidence of distinct biological functions for the ERs is revealed by the contrasting phenotypes observed in the individual lines of ER knockout mice, the ␣ERKO and ␤ERKO, which exhibit phenotypes that generally mirror the respective ER expression patterns (5). The most striking phenotypes in the female ␣ERKO mice include estrogen insensitivity (leading to hypoplasia) in the reproductive tract, hypergonadotropic hypergonadism, lack of pubertal mammary gland development, and excess adipose tissue, whereas in the male, testicular degeneration and epididymal dysfunction are major factors (5). These phenotypes combined with severe deficits in sexual behavior result in complete infertility in both sexes of the ␣ERKO. In contrast, ␤ERKO males are fertile and to date show no obvious phenotypes; however, ␤ERKO females exhibit inefficient ovarian function and subfertility. Interestingly, compound knockout mice (␣␤ERKO) exhibit phenotypes that most heavily resemble those of the ␣ERKO, with the exception of the ovarian phenotype, characterized by progressive germ cell loss accompanied by redifferentiation of the surrounding somatic cells, suggesting a requisite role for both ER forms in this tissue (6, 7).With the cloning of the first ER cDNA 15 years ago has come an immense appreciation of the complex molecular mechanisms underlying the diverse physiological actions of E 2 and the multitude of synthetic ER ligands. This minireview wi...

The human estrogen receptor alpha (ERalpha) and the recently identified ERbeta share a high degree of amino acid homology; however, there are significant differences in regions of these receptors that would be expected to influence transcriptional activity. Consequently, we compared the mechanism(s) by which these receptors regulate target gene transcription, and evaluated the cellular consequences of coexpression of both ER subtypes. Previously, it has been determined that ERalpha contains two distinct activation domains, ERalpha-AF-1 and ERalpha-AF-2, whose transcriptional activity is influenced by cell and promoter context. We determined that ERbeta, like ERalpha, contains a functional AF-2, however, the ERbeta-AF-2 domain functions independently within the receptor. Of additional significance was the finding that ERbeta does not contain a strong AF-1 within its amino-terminus but, rather, contains a repressor domain that when removed, increases the overall transcriptional activity of the receptor. The importance of these findings was revealed when it was determined that ERbeta functions as a transdominant inhibitor of ERalpha transcriptional activity at subsaturating hormone levels and that ERbeta decreases overall cellular sensitivity to estradiol. Additionally, the partial agonist activity of tamoxifen manifest through ERalpha in some contexts was completely abolished upon coexpression of ERbeta. In probing the mechanisms underlying ERbeta-mediated repression of ERalpha transcriptional activity we have determined that 1) ERalpha and ERbeta can form heterodimers within target cells; and 2) ERbeta interacts with target gene promoters in a ligand-independent manner. Cumulatively, these data indicate that one role of ERbeta is to modulate ERalpha transcriptional activity, and thus the relative expression level of the two isoforms will be a key determinant of cellular responses to agonists and antagonists.

BackgroundLeptospirosis is a worldwide zoonotic infection that has been recognized for decades, but the problem of the disease has not been fully addressed, particularly in resource-poor, developing countries, where the major burden of the disease occurs. This paper presents an overview of the current situation of leptospirosis in the region. It describes the current trends in the epidemiology of leptospirosis, the existing surveillance systems, and presents the existing prevention and control programs in the Asia Pacific region.MethodsData on leptospirosis in each member country were sought from official national organizations, international public health organizations, online articles and the scientific literature. Papers were reviewed and relevant data were extracted.ResultsLeptospirosis is highly prevalent in the Asia Pacific region. Infections in developed countries arise mainly from occupational exposure, travel to endemic areas, recreational activities, or importation of domestic and wild animals, whereas outbreaks in developing countries are most frequently related to normal daily activities, over-crowding, poor sanitation and climatic conditions.ConclusionIn the Asia Pacific region, predominantly in developing countries, leptospirosis is largely a water-borne disease. Unless interventions to minimize exposure are aggressively implemented, the current global climate change will further aggravate the extent of the disease problem. Although trends indicate successful control of leptospirosis in some areas, there is no clear evidence that the disease has decreased in the last decade. The efficiency of surveillance systems and data collection varies significantly among the countries and areas within the region, leading to incomplete information in some instances. Thus, an accurate reflection of the true burden of the disease remains unknown.

Recent clinical studies estimate that 60-70% of human ovarian and breast cancers overexpress the estrogen receptor (ER). However, despite the established mitogenic effects of estrogen in these tumors, proliferative markers of hormone action are limited. In the current study, we report that the growth stimulatory cytokine stromal cell-derived factor 1 (SDF-1) is a bona fide target of estrogen action in ERalpha-positive human ovarian and breast cancer cells. Notably, estradiol treatment of BG-1 (ovarian carcinoma) and MCF-7 (breast carcinoma) cells leads to rapid and robust induction of the SDF-1alpha and beta isoforms. This response is blocked by the pure ER antagonist ICI 182,780 and is not apparent in ER-negative ovarian cells, indicating that SDF-1 regulation is ERalpha mediated. Treatment with the protein synthesis inhibitor cycloheximide had no effect on estradiol induction of induction of SDF-1 mRNA levels mRNA levels, demonstrating that SDF-1 is a direct target of ERalpha. SDF-1 protein levels, although undetectable under basal conditions, were strikingly increased by hormone both intracellularly and in the media of cultured BG-1 and MCF-7 cells. In cell proliferation assays, the mitogenic effects of estradiol were neutralized by addition of an SDF-1 antibody and mimicked by the addition of exogenous SDF-1 protein, indicating that SDF-1 mediates the proliferative actions of hormone. Furthermore, activation of the SDF-1 receptor CXCR4 stimulated BG-1 and MCF-7 cell proliferation in a manner comparable to estradiol. Taken together, these results demonstrate a novel estrogen-mediated paracrine pathway for inducing cancer cell proliferation and suggest that SDF-1 and CXCR4 may represent novel therapeutic targets in ERalpha-positive ovarian and breast tumors.