RESUMEN
Overexpression of the human REL transcription factor can malignantly transform chicken spleen cells in vitro. In this report, we have created and characterized a cDNA encoding a chimeric protein (RELDelta424-490-ER) in which sequences of a highly transforming REL mutant (RELDelta424-490) are fused to the ligand-binding domain of the human estrogen receptor (ER). Surprisingly, RELDelta424-490-ER is constitutively nuclear in A293 cells, and RELDelta424-490-ER activates transcription in the absence, but not in the presence, of estrogen in kappaB-site reporter gene assays. Furthermore, RELDelta424-490-ER transforms chicken spleen cells in the absence of estrogen, but the addition of estrogen blocks the ability of RELDelta424-490-ER-transformed cells to form colonies in soft agar, even though estrogen induces increased nuclear translocation of RELDelta424-490-ER in these cells. ERalpha can also inhibit REL-dependent transactivation in trans in an estrogen-dependent manner, and ERalpha can interact with REL in vitro. Thus, the RELDelta424-490-ER fusion protein shows an unusual, reverse hormone regulation, in that its most prominent biological activities (transformation and transactivation) are inhibited by estrogen, probably due to an estrogen-induced interaction between the ER sequences and sequences in the Rel homology domain. Nevertheless, these results indicate that the continual activity of REL is required to sustain the transformed state of chicken spleen cells in culture, suggesting that direct and specific inhibitors of REL may have therapeutic efficacy in certain human lymphoid cancers.
Asunto(s)
Proteínas Oncogénicas v-rel/fisiología , Receptores de Estrógenos/fisiología , Proteínas Recombinantes de Fusión/fisiología , Bazo/metabolismo , Animales , Transformación Celular Neoplásica , Pollos , Humanos , Proteínas Oncogénicas v-rel/genética , Receptores de Estrógenos/genética , Proteínas Recombinantes de Fusión/genética , Bazo/citologíaRESUMEN
Shaping a developing organ or embryo relies on the spatial regulation of cell division and shape. However, morphogenesis also occurs through changes in cell-neighbourhood relationships produced by intercalation. Intercalation poses a special problem in epithelia because of the adherens junctions, which maintain the integrity of the tissue. Here we address the mechanism by which an ordered process of cell intercalation directs polarized epithelial morphogenesis during germ-band elongation, the developmental elongation of the Drosophila embryo. Intercalation progresses because junctions are spatially reorganized in the plane of the epithelium following an ordered pattern of disassembly and reassembly. The planar remodelling of junctions is not driven by external forces at the tissue boundaries but depends on local forces at cell boundaries. Myosin II is specifically enriched in disassembling junctions, and its planar polarized localization and activity are required for planar junction remodelling and cell intercalation. This simple cellular mechanism provides a general model for polarized morphogenesis in epithelial organs.