9 research outputs found
Regulation of gene transcription by NF-kB and stats downstream of the ret receptor tyrosinekinase in hirschsprung disease and thyroid cancer
Changes of ATP and ADP in cultured astrocytes under and after in vitro ischemia
A very large body of evidence from in vivo studies has been accumulated on a link between the change of energy and cell survival/apoptosis. Using an in vitro ischemia model, we have previously shown that ischemia could induce apoptosis in astrocytes. In this study, we utilized the same in vitro model to investigate changes in ATP and ADP levels in cultured astrocytes and attempted to demonstrate an energy-cell death linkage. Astrocytes remained unaltered after 2 hr of ischemia but were moderately or severely damaged after 4 or 6-8 hr, respectively. The astrocytes that survived various lengths of in vitro ischemic incubation retained their ability to produce ATP after ischemia. Both ATP and ADP levels were increased in astrocytes that remained alive under in vitro ischemia for over 6 hr. The largest decline in the percent of viable astrocytes during ischemia corresponded well to the reduction in ATP and ADP levels in these cultures
TTF-1 and RET promoter SNPs: Regulation of RET transcription in Hirschsprung's disease
Single nucleotide polymorphisms (SNPs) of the coding regions of receptor tyrosine kinase gene (RET) are associated with Hirschsprung's disease (HSCR, aganglionic megacolon). These SNPs, individually or combined, may act as a low penetrance susceptibility locus and/or be in linkage disequilibrium (LD) with another susceptibility locus located in RET regulatory regions. Because two RET promoter SNPs have been found associated with HSCR, in LD with HSCR-associated RET coding region haplotypes, their implication in the transcriptional regulation of RET is of major interest. Analysis of 172 sporadic HSCR patients also revealed the presence of HSCR-associated RET promoter SNPs in LD with the main coding region RET haplotype observed in Chinese patients. By using a weighted logistic regression approach, we determined that of all SNPs tested in our study, the promoter SNPs are the most correlated to the disease. Functional analysis of the RET promoter SNPs in the context of additional 5′ regulatory regions demonstrated that the HSCR-associated alleles decrease RET transcription. These SNPs overlap a TTF-1 binding site and TTF-1-activated RET transcription is also decreased by the HSCR-associated SNPs. Moreover, we identified an HSCR patient with a Gly322Ser TTF-1 mutation that compromises activation of transcription from HSCR-associated RET promoter haplotypes. Interestingly, we show that the pattern of RET and TTF-1 expression is coincident in developing human gut. We also present a detailed profile of the RET gene in our population, which provides an insight into the higher incidence of the disease in China. © Oxford University Press 2005; all rights reserved.link_to_subscribed_fulltex