RESUMEN
Nucleoporin Nup154 is a Drosophila component of the nuclear pore complex (NPC), evolutionarily conserved from yeast to humans. While functional studies carried out in both yeast and metazoan cells indicated that Nup154 homologs are key elements of the NPC framework, the striking phenotypic specificity displayed by nup154 hypomorphic mutant alleles suggested that Nup154 might play additional roles in the context of the NPC. Actually, genetic analyses demonstrated that mutant nurse-cell nuclei do not undergo a normal chromosome dispersal process, uncovering an essential requirement for nup154 gene function during oogenesis. In this report, we show that Nup154 interacts genetically and physically with Cup, a germline-specific protein implicated in multiple aspects of female gametogenesis, including the regulation of the nurse-cell chromosome structure. The two proteins colocalize in vivo and are co-immunoprecipitated from ovarian extracts. Moreover, cup, nup154 double mutants exhibit much stronger oogenesis defects than single mutants. Our findings delineate an intriguing scenario where an ubiquitous nucleoporin might directly influence specialized developmental events.
Asunto(s)
Proteínas de Drosophila/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/genética , Proteínas de Complejo Poro Nuclear/genética , Oogénesis/genética , Animales , Animales Modificados Genéticamente , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citología , Drosophila melanogaster/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Genes de Insecto , Proteínas Fluorescentes Verdes/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Oogénesis/fisiología , Proteínas Recombinantes/genéticaRESUMEN
BACKGROUND: Chromosomal instability is one of the most common features of prostate cancer (PC), especially in advanced stages. Recent studies suggest that defects in mitotic checkpoints play a role in carcinogenesis. Lack of mitotic regulation induces aneuploidy in cancer cells acting thereafter as a driving force for malignant progression. Serine/threonine protein kinases of the Aurora genes family play an important throughout the entire cell cycle. In that Aurora B regulates chromosome segregation by ensuring the orientation of sister chromatids. As a consequence, the overexpression of Aurora B in diploid human cells NHDF induces the appearance of multinucleate cells. METHODS: Archive samples of normal and neoplastic prostate tissue, and prostate derived cell lines were screened for the expression of Aurora B. RESULTS: Immunohistochemical analysis showed increased nuclear expression of Aurora-B in high Gleason grade PCs respect to low and intermediate grade cases and in all cancers in respect to hyperplastic and normal glands. Furthermore, in the high Gleason grade anaplastic cancer tissues Aurora B expression was accompanied by the phosphorylation of the histone H3. In analogy to the in vivo situation, Aurora B was vigorously expressed in the androgen independent PC cell lines PC3 and DU145, while a very modest expression of the kinase was observed in the androgen sensitive LnCap cells and in the EPN cells, a line of epithelial cells derived from normal prostate tissue. In addition, in PC3 cells Aurora B expression is accompanied the by the phosphorylation of the histone H3. The block of Aurora B expression induced by an inhibitor of Aurora kinase activity significantly reduced the growth of prostate carcinoma cells, but not that of non-transformed EPN cells. CONCLUSIONS: Our data are the first demonstration of a role of Aurora B in PC progression. In addition, the observation that Aurora B specific inhibitors interfere with PC cell proliferation but not with that of non-transformed prostate epithelial cells suggest that Aurora B is a potential therapeutic target for PC.
