The aryl hydrocarbon (Ah) receptor (AHR) mediates many carcinogenic and teratogenic effects of environmentally toxic chemicals such as dioxin. An AHR-deficient (Ahr-/-) mouse line was constructed by homologous recombination in embryonic stem cells. Almost half of the mice died shortly after birth, whereas survivors reached maturity and were fertile. The Ahr-/- mice showed decreased accumulation of lymphocytes in the spleen and lymph nodes, but not in the thymus. The livers of Ahr-/- mice were reduced in size by 50 percent and showed bile duct fibrosis Ahr-/- mice were also nonresponsive with regard to dioxin-mediated induction of genes encoding enzymes that catalyze the metabolism of foreign compounds. Thus, the AHR plays an important role in the development of the liver and the immune system.
A growth factor specific for epithelial cells was identified in conditioned medium of a human embryonic lung fibroblast cell line. The factor, provisionally termed keratinocyte'growth factor (KGF) because of its predominant activity on this cell type, was purified to homogeneity by a combination of ultrafiltration, heparin-Sepharose affinity chromatography, and hydrophobic chromatography on a C4 reversed-phabe HPLC column. KGF was both acid and heat labile and consisted of a single polypeptide chain of =28 kDa. Purified KGF was a potent mitogen for epithelial cells, capable of stimulating DNA synthesis in quiescent BALB/MK epidermal keratinocytes by >500-fold with activity detectable at 0.1 nM and maximal at 1.0 nM. Lack of mitogenic activity on either fibroblasts or endothelial cells indicated that KGF possessed a target cell specificity distinct from any previously characterized growth factor. Microsequencing' revealed an amino-terminal squence containing no significant homology to any known protein. The release of this growth factor by human embryonic fibroblasts raises the possibility that KGF may play a role in mesenchymal stimlation of normal epithelial cell proliferation.Growth factors are important mediators of intercellular communication. These potent molecules are generally released by qne cell type and act to influence proliferation of other cell types (1). Interest in growth factors has been heightened by evidence of their potential involvement in neoplasia.'The v-sis transforming gene of simian sarcoma virus encodes a protein that is homologous to the B chain of platelet-derived growth factor (2,3). Moreover, a number of oncogenes are homologues of genes encoding growth factor receptors (4). Thus, increased understanding of growth factors and their receptor-mediated signal-transduction pathways is likely to provide insights into mechanisms of both normal and malignant cell growth.Recognizing that the vast majority of human malignancies are derived from epithelial tissues (5), we sought to identify growth factors specific for these cell types. In this communication, we report the purification to homogeneity of such a growth factor released by a human embryonic lung fibroblast line. Our demonstration of its unique N-terminal amino acid sequence aInd epithelial cell specificity distinguishes this mitogen from any previously described growth factor.
METHODS AND MATERIALSCell Culture. M426 human embryonic fibroblasts (6), BALB/MK mouse epidermal keratinocytes (7), and NIH 3T3 mouse embryonic fibroblasts (8) were established in this laboratory. CCL208 rhesus monkey bronchial epithelial cells (9) were obtained from the American Type Culture Collection, and the B5/589 human mammary epithelial cell line, prepared as described (10), was a gift from M. Stampfer (Lawrence Berkeley Laboratory). Primary cultures of human saphenous vein endothelial cells were prepared and maintained as described elsewhere (11). Epidermal growth factor (EGF) and insulin were from Collaborative Research, and transforming gro...
Frizzled polypeptides are integral membrane proteins that recently were shown to function as receptors for Wnt signaling molecules. Here, we report the identification of a novel, secreted 36-kDa protein that contains a region homologous to a putative Wnt-binding domain of
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