Promoter methylation of the RAS-association domain family 1, isoform A gene (RASSF1A) is one of the most frequent events found in human tumours. In this study we set out to test the hypothesis that ...loss of Rassf1a can cooperate with inactivation of the adenomatous polyposis coli (Apc) gene to accelerate intestinal tumourigenesis using the Apc-Min (Apc(Min/+)) mouse model, as mutational or deletional inactivation of APC is a frequent early event in the genesis of intestinal cancer. Further, loss of RASSF1A has also been reported to occur in premalignant adenomas of the bowel. RASSF1A has been implicated in an array of pivotal cellular processes, including regulation of the cell cycle, apoptosis, microtubule stability and most recently in the beta-catenin signalling pathway. By interbreeding isoform specific Rassf1a knockout mice with Apc(+/Min) mice, we showed that loss of Rassf1a results in a significant increase in adenomas of the small intestine and accelerated intestinal tumourigenesis leading to the earlier death of adenocarcinoma-bearing mice and decreased overall survival. Comparative genomic hybridization of adenomas from Rassf1a(-/-); Apc(+/Min) mice revealed no evidence of aneuploidy or gross chromosomal instability (no difference to adenomas from Rassf1a(+/+); Apc(+/Min) mice). Immunohistochemical analysis of adenomas revealed increased nuclear beta-catenin accumulation in adenomas from Rassf1a(-/-); Apc(+/Min) mice, compared to those from Rassf1a(+/+); Apc(+/Min) mice, but no differences in proliferation marker (Ki67) staining patterns. Collectively these data demonstrate cooperation between inactivation of Rassf1a and Apc resulting in accelerated intestinal tumourigenesis, with adenomas showing increased nuclear accumulation of beta-catenin, supporting a mechanistic link via loss of the known interaction of Rassf1 with beta-TrCP that usually mediates degradation of beta-catenin.
Promoter methylation of the RAS-association domain family 1, isoform A gene (RASSF1A) is one of the most frequent events found in human tumours. In this study we set out to test the hypothesis that ...loss of Rassf1a can cooperate with inactivation of the adenomatous polyposis coli (Apc) gene to accelerate intestinal tumourigenesis using the Apc-Min (Apc(Min/+)) mouse model, as mutational or deletional inactivation of APC is a frequent early event in the genesis of intestinal cancer. Further, loss of RASSF1A has also been reported to occur in premalignant adenomas of the bowel. RASSF1A has been implicated in an array of pivotal cellular processes, including regulation of the cell cycle, apoptosis, microtubule stability and most recently in the beta-catenin signalling pathway. By interbreeding isoform specific Rassf1a knockout mice with Apc(+/Min) mice, we showed that loss of Rassf1a results in a significant increase in adenomas of the small intestine and accelerated intestinal tumourigenesis leading to the earlier death of adenocarcinoma-bearing mice and decreased overall survival. Comparative genomic hybridization of adenomas from Rassf1a(-/-); Apc(+/Min) mice revealed no evidence of aneuploidy or gross chromosomal instability (no difference to adenomas from Rassf1a(+/+); Apc(+/Min) mice). Immunohistochemical analysis of adenomas revealed increased nuclear beta-catenin accumulation in adenomas from Rassf1a(-/-); Apc(+/Min) mice, compared to those from Rassf1a(+/+); Apc(+/Min) mice, but no differences in proliferation marker (Ki67) staining patterns. Collectively these data demonstrate cooperation between inactivation of Rassf1a and Apc resulting in accelerated intestinal tumourigenesis, with adenomas showing increased nuclear accumulation of beta-catenin, supporting a mechanistic link via loss of the known interaction of Rassf1 with beta-TrCP that usually mediates degradation of beta-catenin. PUBLICATION ABSTRACT
We present a detailed in vivo characterization of hepatocyte transcriptional regulation in HepG2 cells, using chromatin immunoprecipitation and detection on PCR fragment-based genomic tiling path ...arrays covering the encyclopedia of DNA element (ENCODE) regions. Our data suggest that HNF-4α and HNF-3β, which were commonly bound to distal regulatory elements, may cooperate in the regulation of a large fraction of the liver transcriptome and that both HNF-4α and USF1 may promote H3 acetylation to many of their targets. Importantly, bioinformatic analysis of the sequences bound by each transcription factor (TF) shows an over-representation of motifs highly similar to the in vitro established consensus sequences. On the basis of these data, we have inferred tentative binding sites at base pair resolution. Some of these sites have been previously found by in vitro analysis and some were verified in vitro in this study. Our data suggests that a similar approach could be used for the in vivo characterization of all predicted/uncharacterized TF and that the analysis could be scaled to the whole genome.
Promoter methylation of the RAS-association domain family 1, isoform A gene (RASSF1A) is one of the most frequent events found in human tumours. In this study we set out to test the hypothesis that ...loss of Rassf1a can cooperate with inactivation of the adenomatous polyposis coli (Apc) gene to accelerate intestinal tumourigenesis using the Apc-Min (Apc super(Min/+)) mouse model, as mutational or deletional inactivation of APC is a frequent early event in the genesis of intestinal cancer. Further, loss of RASSF1A has also been reported to occur in premalignant adenomas of the bowel. RASSF1A has been implicated in an array of pivotal cellular processes, including regulation of the cell cycle, apoptosis, microtubule stability and most recently in the beta-catenin signalling pathway. By interbreeding isoform specific Rassf1a knockout mice with Apc super(+/Min) mice, we showed that loss of Rassf1a results in a significant increase in adenomas of the small intestine and accelerated intestinal tumourigenesis leading to the earlier death of adenocarcinoma-bearing mice and decreased overall survival. Comparative genomic hybridization of adenomas from Rassf1a super(-/-); Apc super(+/Min) mice revealed no evidence of aneuploidy or gross chromosomal instability (no difference to adenomas from Rassf1a super(+/+); Apc super(+/Min) mice). Immunohistochemical analysis of adenomas revealed increased nuclear beta-catenin accumulation in adenomas from Rassf1a super(-/-); Apc super(+/Min) mice, compared to those from Rassf1a super(+/+); Apc super(+/Min) mice, but no differences in proliferation marker (Ki67) staining patterns. Collectively these data demonstrate cooperation between inactivation of Rassf1a and Apc resulting in accelerated intestinal tumourigenesis, with adenomas showing increased nuclear accumulation of beta-catenin, supporting a mechanistic link via loss of the known interaction of Rassf1 with beta-TrCP that usually mediates degradation of beta-catenin.
Promoter methylation of the RAS-association domain family 1, isoform A gene (RASSF1A) is one of the most frequent events found in human tumours. In this study we set out to test the hypothesis that ...loss of Rassf1a can cooperate with inactivation of the adenomatous polyposis coli (Apc) gene to accelerate intestinal tumourigenesis using the Apc-Min (Apc super(Min/+)) mouse model, as mutational or deletional inactivation of APC is a frequent early event in the genesis of intestinal cancer. Further, loss of RASSF1A has also been reported to occur in premalignant adenomas of the bowel. RASSF1A has been implicated in an array of pivotal cellular processes, including regulation of the cell cycle, apoptosis, microtubule stability and most recently in the b-catenin signalling pathway. By interbreeding isoform specific Rassf1a knockout mice with Apc super(+/Min) mice, we showed that loss of Rassf1a results in a significant increase in adenomas of the small intestine and accelerated intestinal tumourigenesis leading to the earlier death of adenocarcinoma-bearing mice and decreased overall survival. Comparative genomic hybridization of adenomas from Rassf1a super(-/-); Apc super(+/Min) mice revealed no evidence of aneuploidy or gross chromosomal instability (no difference to adenomas from Rassf1a super(+/+); Apc super(+/Min) mice). Immunohistochemical analysis of adenomas revealed increased nuclear b-catenin accumulation in adenomas from Rassf1a super(-/-); Apc super(+/Min) mice, compared to those from Rassf1a super(+/+); Apc super(+/Min) mice, but no differences in proliferation marker (Ki67) staining patterns. Collectively these data demonstrate cooperation between inactivation of Rassf1a and Apc resulting in accelerated intestinal tumourigenesis, with adenomas showing increased nuclear accumulation of b-catenin, supporting a mechanistic link via loss of the known interaction of Rassf1 with b-TrCP that usually mediates degradation of b-catenin.Oncogene (2008) 27, 4503-4508; doi:10.1038/onc.2008.94; published online 7 April 2008
The eighth assignment 1943-1945 Dovey, H. O.
Intelligence and national security,
04/1997, Letnik:
12, Številka:
2
Journal Article
Recenzirano
The A Force had a large share in the deception operations to cover the Allied landings in North Africa at the end of 1942, and this marked the way to its main area of activity in 1943. In 1943, the A ...Force was chiefly concerned with General Dwight D. Eisenhower's HQ in Algiers. It was reorganised to suit its new duties. Some of its escapades in the 1943-1945 period are discussed.
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