ABSTRACT
A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominant-negative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 'gain of function' (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53(R175H) mutant expression resulted in the upregulation of cell cycle progression genes. A second group, which was upregulated exclusively by mutant p53(R175H), was predominantly enriched in developmental genes. This group of genes included the Twist1, a regulator of metastasis and epithelial-mesenchymal transition (EMT). Twist1 levels were also elevated in metastatic prostate cancer-derived cell line DU145, in immortalized lung fibroblasts and in a subset of lung cancer samples, all in a mutant p53-dependent manner. p53(R175H) mutant bearing immortalized epithelial cells showed typical features of EMT, such as higher expression of mesenchymal markers, lower expression of epithelial markers and enhanced invasive properties in vitro. The mechanism by which p53(R175H) mutant induces Twist1 expression involves alleviation of the epigenetic repression. Our data suggest that Twist1 expression might be upregulated following p53 mutation in cancer cells.
Subject(s)
Epithelial-Mesenchymal Transition , Nuclear Proteins/metabolism , Prostatic Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Twist-Related Protein 1/metabolism , Amino Acid Substitution , Cell Line, Transformed , Cell Line, Tumor , Epigenesis, Genetic , Histones/metabolism , Humans , Male , Mutation , Nuclear Proteins/genetics , Polycomb Repressive Complex 1 , Promoter Regions, Genetic , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins/metabolism , Repressor Proteins/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/physiology , Twist-Related Protein 1/genetics , Up-RegulationABSTRACT
Bioerosion by boring sponges is an important mechanism shaping the structure of coral reefs all around the world. To determine the excavation rate by boring sponges, we developed a system in which chemical and mechanical boring rates [calcium carbonate (CaCO(3)) dissolution and chip production, respectively] were measured simultaneously in experimental tanks containing reefal rock inhabited by a boring sponge. Pione cf. vastifica (Hancock 1849) was chosen as a model species to study the erosion rate of boring sponges. It is an abundant species in the coral reefs of the Nature Reserve Reef, Elat, Gulf of Aqaba, northern Red Sea, reaching maximum abundance at 25-30 m. The rate of chemical bioerosion was determined from the increase in tank-seawater alkalinity over time, and the mechanical bioerosion rate was estimated from the total amount of CaCO(3) chips produced over the same time interval. The measured bioerosion rate of P. cf. vastifica was 2.3 g m(-2) sponge day(-1), showing seasonal but not diurnal variations, suggesting that the zooxanthellae harboring the sponge have no effect on its boring rate. The experiments indicated clearly that per each mass of chips that P. cf. vastifica produces during its boring activity, it dissolves three masses of reef CaCO(3) framework. Assuming that some additional boring sponges can use a similar strategy of bioerosion, these findings suggest that chips, the most obvious erosion products of boring sponges, represent only a small fraction of boring sponge bioerosion capacity.
