Wnt/Wingless signaling controls many fundamental processes during animal development. Wnt transduction is mediated by the association of beta-catenin with nuclear TCF DNA binding factors. Here we report the identification of two segment polarity genes in Drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for Wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human BCL9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking Pygo to beta-catenin. Our results suggest that the recruitment of Pygo permits beta-catenin to transcriptionally activate Wnt target genes and raise the possibility that a deregulation of these events may play a causal role in the development of B cell malignancies.
The Drosophila seven in absentia (sina) gene is required for R7 photoreceptor cell formation during Drosophila eye development, where it functions within the Ras/Raf pathway and targets other proteins for degradation via associations with a ubiquitinconjugating enzyme. Recently, a mammalian sina homologue was reported to be a p53-
Prostate cancer is the most common malignancy in the United States and the second leading cause of cancer-related death among men (1). The normal prostate gland contains a two-layer epithelium composed of a population of small round stem cells called basal cells, which line the basement membrane, and a population of larger differentiated epithelial cells called secretory cells, which secrete a variety of proteins and other substances into the lumen of the gland (2, 3). Although both basal and secretory cells contain androgen receptors (AR) 1 (4, 5), only the luminal secretory epithelial cells are dependent on steroid hormone for their function, growth, and survival (4). In the absence of testosterone or related androgens, which can serve as ligands for AR, the secretory cells undergo rapid programmed cell death (6). Current treatment for metastatic adenocarcinoma of the prostate is predicated on the cell deathinducing effects of anti-androgens and hormone-ablative measures, which reduce endogenous production of androgens. However, nearly all hormone-dependent prostate cancers eventually relapse as fatal hormone-independent disease (7).Multiple, still largely unidentified mechanisms may account for the complete independence or reduced dependence of prostate cancers on androgens (reviewed in Refs. 8 -10). AR gene deletion or sequestration of the AR from the nucleus to the cytoplasm have been described in some hormone-independent tumors, implying that genetic alterations associated with tumor progression can abrogate the necessity for AR in some cases. However, many tumors may rely on other strategies that allow cancer cells to grow in low concentrations of androgens, including AR gene amplification or overexpression (11,12) and AR mutations that permit transactivation of target genes with little or no requirement for steroid hormones (9, 13). Since most hormone-insensitive prostate cancers still retain a wild-type AR, presumably alterations in the factors that control the levels of AR and its function appear to play a major role in resistance to anti-androgen and hormone-ablative therapies. Thus, a need exists to understand more about the molecular mechanisms that govern the activity of AR.Steroid hormones mediate their effects by binding to specific intracellular receptors that act as hormone-dependent transcription factors. Upon binding steroid ligands, the AR undergo a conformational change, translocate to the nucleus, and bind to specific DNA sequences located near or in promoter regions of target genes. After binding DNA, the receptor interacts with components of the basal transcription machinery and sometimes sequence-specific transcription factors, resulting in positive or negative effects on gene transcription (14,15). A number of proteins have been identified that associate with the inactive or hormone-bound hormone-receptor complexes, including several heat shock family proteins and various types of transcription co-activators (reviewed in Refs. 16 and 17). However, many details remain unclear as to the ...
BAG-1 (also known as RAP46) is an anti-apoptotic protein, which has been shown previously to interact with a number of nuclear hormone receptors, including receptors for glucocorticoid, estrogen, and thyroid hormone. We show here that BAG-1 also interacts with retinoic acid receptor (RAR). Gel retardation assays demonstrated that in vitro translated BAG-1 protein could effectively inhibit the binding of RAR but not retinoid X receptor (
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