| 1. |
- Bard-Chapeau, Emilie A, et al.
(författare)
-
Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model.
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:1
-
Tidskriftsartikel (refereegranskat)abstract
- The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important for human HCC, with a striking 1,199 genes being linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.
|
|
| 2. |
- Sayadi, Ahmed, et al.
(författare)
-
Zip14 expression induced by lipopolysaccharides in macrophages attenuates inflammatory response
- 2013
-
Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1023-3830 .- 1420-908X. ; 62:2
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE AND DESIGN: We investigated the role and regulation of zinc transporters in the activation of the inflammatory response in macrophages. Our exploratory computational study found that Zip14 (SLC39A14) was consistently up-regulated in activated macrophages; we therefore focused subsequently on that gene in the mechanistic study.MATERIAL: The expression and function of Zip14 was assessed in primary macrophages obtained by in-vitro differentiation of monocytes from human blood.METHODS: Primary macrophages were subjected to treatments with lipopolysaccharides, cytokines, chemicals, and pharmacological agents. SLC39A14 and inflammatory cytokine gene expressions were assessed by RT-qPCR. Zip14 siRNA knockdown was performed to explore the gene function.RESULTS: Lipopolysaccharide's inflammatory stimulus was a strong inducer of SLC39A14 mRNA expression in macrophages. This induction was dependent on calcium signaling, GC-rich DNA-binding, and NF-κB down-regulation. Impregnation of lipopolysaccharide-stimulated macrophages with the glucocorticoid dexamethasone further enhanced Zip14 expression while reducing interleukin-6 and tumor necrosis factor-α production. Zip14 knockdown in macrophages attenuated the expression and secretion of cytokines, indicating a buffering function for this zinc transporter.CONCLUSIONS: Collectively, our results identified the zinc transporter Zip14 as expressed downstream of lipopolysaccharide signals in macrophages. Zip14 induction had a regulatory function in cytokine production.
|
|
| 3. |
- Bard-Chapeau, Emilie A, et al.
(författare)
-
Mice carrying a hypomorphic Evi1 allele are embryonic viable but exhibit severe congenital heart defects
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2
-
Tidskriftsartikel (refereegranskat)abstract
- The ecotropic viral integration site 1 (Evi1) oncogenic transcription factor is one of a number of alternative transcripts encoded by the Mds1 and Evi1 complex locus (Mecom). Overexpression of Evi1 has been observed in a number of myeloid disorders and is associated with poor patient survival. It is also amplified and/or overexpressed in many epithelial cancers including nasopharyngeal carcinoma, ovarian carcinoma, ependymomas, and lung and colorectal cancers. Two murine knockout models have also demonstrated Evi1's critical role in the maintenance of hematopoietic stem cell renewal with its absence resulting in the death of mutant embryos due to hematopoietic failure. Here we characterize a novel mouse model (designated Evi1(fl3)) in which Evi1 exon 3, which carries the ATG start, is flanked by loxP sites. Unexpectedly, we found that germline deletion of exon3 produces a hypomorphic allele due to the use of an alternative ATG start site located in exon 4, resulting in a minor Evi1 N-terminal truncation and a block in expression of the Mds1-Evi1 fusion transcript. Evi1(δex3/δex3) mutant embryos showed only a mild non-lethal hematopoietic phenotype and bone marrow failure was only observed in adult Vav-iCre/+, Evi1(fl3/fl3) mice in which exon 3 was specifically deleted in the hematopoietic system. Evi1(δex3/δex3) knockout pups are born in normal numbers but die during the perinatal period from congenital heart defects. Database searches identified 143 genes with similar mutant heart phenotypes as those observed in Evi1(δex3/δex3) mutant pups. Interestingly, 42 of these congenital heart defect genes contain known Evi1-binding sites, and expression of 18 of these genes are also effected by Evi1 siRNA knockdown. These results show a potential functional involvement of Evi1 target genes in heart development and indicate that Evi1 is part of a transcriptional program that regulates cardiac development in addition to the development of blood.
|
|
