Overexpression of hepatoma-derived growth factor in melanocytes does not lead to oncogenic transformation

<p>Abstract</p> <p>Background</p> <p>HDGF is a growth factor which is overexpressed in a wide range of tumors. Importantly, expression levels were identified as a prognostic marker in some types of cancer such as melanoma.</p> <p>Methods</p> <p>To investigate the presumed oncogenic/transforming capacity of HDGF, we generated transgenic mice overexpressing HDGF in melanocytes. These mice were bred with mice heterozygous for a defective copy of the Ink4a tumor suppressor gene and were exposed to UV light to increase the risk for tumor development both genetically and physiochemically. Mice were analyzed by immunohistochemistry and Western blotting. Furthermore, primary melanocytes were isolated from different strains created.</p> <p>Results</p> <p>Transgenic animals overexpressed HDGF in hair follicle melanocytes. Interestingly, primary melanocytes isolated from transgenic animals were not able to differentiate <it>in vitro </it>whereas cells isolated from wild type and HDGF-deficient animals were. Although, HDGF^-/-/Ink4a^+/-mice displayed an increased number of epidermoid cysts after exposure to UV light, no melanomas or premelanocytic alterations could be detected in this mouse model.</p> <p>Conclusions</p> <p>The results therefore provide no evidence that HDGF has a transforming capacity in tumor development. Our results in combination with previous findings point to a possible role in cell differentiation and suggest that HDGF promotes tumor progression after secondary upregulation and may represent another protein fitting into the concept of non-oncogene addiction of tumor tissue.</p

Fibroblast growth factor signalling controls nervous system patterning and pigment cell formation in Ciona intestinalis

During the development of the central nervous system (CNS), combinations of transcription factors and signalling molecules orchestrate patterning, specification and differentiation of neural cell types. In vertebrates, three types of melanin-containing pigment cells, exert a variety of functional roles including visual perception. Here we analysed the mechanisms underlying pigment cell specification within the CNS of a simple chordate, the ascidian Ciona intestinalis. Ciona tadpole larvae exhibit a basic chordate body plan characterized by a small number of neural cells. We employed lineage-specific transcription profiling to characterize the expression of genes downstream of fibroblast growth factor signalling, which govern pigment cell formation. We demonstrate that FGF signalling sequentially imposes a pigment cell identity at the expense of anterior neural fates. We identify FGF-dependent and pigment cell-specific factors, including the small GTPase, Rab32/38 and demonstrated its requirement for the pigmentation of larval sensory organs

BRAF Activation Initiates but Does Not Maintain Invasive Prostate Adenocarcinoma

Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAFV600E–a mutation found in ∼10% of human prostate tumors–was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAFV600E in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAFV600E is not required for its maintenance

Variable Kalkulationsmethodik zur Analyse von Kunststoffrecyclingverfahren anhand von wirtschaftlichen und umweltrelevanten Kriterien

Available from TIB Hannover: RN 8423(45) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Regulation of the tyrosinase promoter in transgenic mice: expression of a tyrosinase-lacZ fusion gene in embryonic and adult brain

The enzyme tyrosinase is indispensable for pigmentation and the gene is expressed mainly in pigment cells. Regulatory elements, at -12 to -15 kb (enhancer) and within the 270 bp directly upstream of the transcription start site, have been described recently and their importance demonstrated in transgenic experiments. We were interested in tyrosinase promoter activity during development and used beta-galactosidase as reporter gene. Transgenic mice were generated carrying a tyrosinase-lacZ fusion gene, containing 6.1 kb of tyrosinase 5' sequences. In transgenic embryos, beta-galactosidase activity was detected along the entire neural tube, with the most prominent expression in the developing telencephalon, and also in the adult brain. Equivalent expression was observed in the developing retina. Tyrosinase protein was identified in embryonic and adult brain, but no DOPAoxidase or tyrosine hydroxylase activity was detected. From our results we conclude that 1) tyrosinase protein is present in embryonic and adult mouse brain and 2) the tyrosinase promoter can direct expression of a reporter gene to pigment cells and neural tissues

Tyrosinase, the key enzyme in melanin synthesis, is expressed in murine brain

Tyrosinase is one of the key enzymes in mammalian melanin synthesis. The pigment is produced in two different cell types: the pigmented epithelial cell of the retina, and the melanocyte, a cell of neural-crest origin. We recently showed that a fusion gene between regulatory sequences of tyrosinase gene (tyr) and the beta-galactosidase gene (lacZ), when introduced into transgenic mice, resulted in embryonic expression in presumptive pigment cells but also in cells populations along the entire neural tube. This expression in the developing brain was striking, and we therefore asked whether this would still be detectable after birth. Transgenic mice carrying the tyr-lacZ fusion gene showed beta-galactosidase expression in adult brain. On Western blots, we detected tyrosinase-specific bands of 65-68 kDa in brain and eye. Using an affinity-purified antibody, we showed that detection of tyrosinase is specific and competed off by the presence of the cognate tyrosinase-derived peptide. However, neither tyrosine hydroxylase nor Dopa oxidase activity were detected in protein extracts of brain. We therefore suggest that tyrosinase is present in brain but either not functional or catalyzing different reactions compared to pigment cells