21 research outputs found
The PDGF alpha receptor 1,5 kb transcript: target for molecular detection of testicular germ cell tumours of adolescents and adults
The PDGF alpha receptor 1,5 kb transcript: target for molecular detection of testicular germ cell tumours of adolescents and adults
Autocrine production of prostaglandin F\u3csub\u3e2α\u3c/sub\u3e enhances phenotypic transformation of normal rat kidney fibroblasts
\u3cp\u3eWe have used normal rat kidney (NRK) fibroblasts as an in vitro model system to study cell transformation. These cells obtain a transformed phenotype upon stimulation with growth-modulating factors such as retinoic acid (RA) or transforming growth factor-β (TGF-β). Patch-clamp experiments showed that transformation is paralleled by a profound membrane depolarization from around -70 to -20 mV. This depolarization is caused by a compound in the medium conditioned by transformed NRK cells, which enhances intracellular Ca \u3csup\u3e2+\u3c/sup\u3e levels and thereby activates Ca\u3csup\u3e2+\u3c/sup\u3e-dependent Cl \u3csup\u3e-\u3c/sup\u3e channels. This compound was identified as prostaglandin F \u3csub\u3e2α\u3c/sub\u3e (PGF\u3csub\u3e2α\u3c/sub\u3e) using electrospray ionization mass spectrometry. The active concentration in the medium conditioned by transformed NRK cells as determined using an enzyme immunoassay was 19.7 ± 2.5 nM (n = 6), compared with 1.5 ± 0.1 nM (n = 3) conditioned by nontransformed NRK cells. Externally added PGF\u3csub\u3e2α\u3c/sub\u3e was able to trigger NRK cells that had grown to density arrest to restart their proliferation. This proliferation was inhibited when the FP receptor (i.e., natural receptor for PGF\u3csub\u3e2\u3c/sub\u3eα) was blocked by AL-8810. RA-induced phenotypic transformation of NRK cells was partially (∼25%) suppressed by AL-8810. Our results demonstrate that PGF\u3csub\u3e2α\u3c/sub\u3e acts as an autocrine enhancer and paracrine inducer of cell transformation and suggest that it may play a crucial role in carcinogenesis in general.\u3c/p\u3
Haplotype-specific expression of the human PDGFRA gene correlates with the risk of glioblastomas
Aberrant expression of the platelet-derived growth factor a-receptor (PDGFRA) gene has been associated with various diseases, including neural tube defects and gliomas. We have previously identified 5 distinct haplotypes for the PDGFRA promoter region, designated H1, H2 alpha, H2 beta, H2 gamma and H2 delta. Of these haplotypes H1 and H2 alpha: are the most common, whereby H1 drives low and H2 alpha high transcriptional activity in transient transfection assays. Here we have investigated the role of these PDGFRA promoter haplotypes in gliomagenesis at both the genetic and cellular level. In a case-control study on 71 glioblastoma patients, we observed a clear underrepresentation of H1 alleles, with pH1 = 0.141 in patients and pH1 = 0.211 in a combined Western European control group (n = 998, p < 0.05). Furthermore, in 3 out of 4 available H1/H2 alpha heterozygous human glioblastoma cell lines, H1-derived mRNA levels were more than 10-fold lower than from H2 alpha, resulting at least in part from haplotype-specific epigenetic differences such as DNA methylation and histone acetylation. Together, these results indicate that PDGFRA promoter haplotypes may predispose to gliomas. We propose a model in which PDGFRA is upregulated in a haplotype-specific manner during neural stem cell differentiation, which affects the pool size of cells that can later undergo gliomagenesis. (C) 2008 Wiley-Liss, Inc