Conditional hepatocarcinogenesis in mice expressing SV 40 early sequences.

We closely mimicked the in vivo setting in which sporadic hepatocarcinoma occurs by establishing a transgenic mouse model carrying regulatable SV40 early sequences under the control of the regulatory sequences of the human antithrombin III gene that confer hepatic expression. In this system, floxed dormant oncogenic sequences became functional after excision due to adenoviral expression of Cre recombinase or the stable transgenic expression in liver of a tamoxifen-inducible Cre. Hepatic oncogene expression was switched on by both methods, leading to the development of hepatocellular carcinoma.

In vivo functional characterization of the aldolase B gene enhancer.

A 400-bp intronic enhancer fragment in conjunction with the proximal promoter of the aldolase B gene provided correct tissue-specific expression in transgenic mice together with hormonal regulation in the liver. We investigated in vivo and in cultured cells the contribution of the intronic regulatory sequences and their interaction with the promoter elements in controlling aldolase B gene expression. Transgene activity was completely abolished by disruption of the two hepatocyte nuclear factor 1 (HNF1) binding sites in the enhancer, whereas mutation of one HNF1 site had no effect in the liver but strongly decreased activity in the kidney.

A tamoxifen-inducible chimeric Cre recombinase specifically effective in the fetal and adult mouse liver.

The spatiotemporal control of somatic mutagenesis in mice is considered a promising step to determine the function of a given gene product in a defined population of cells at any given time during animal life and also to generate better mouse models of human diseases. To introduce defined mutations in a temporally controlled manner in the liver, we established transgenic mice expressing a tamoxifen-inducible Cre recombinase under the control of the transthyretin promoter (TTR-Cre ind). The recombinase activity was examined on 2 different floxed alleles by crossing TTR-Cre ind mice with either the reporter strain ROSA 26 or with homozygous mice carrying floxed catalytic alpha2 subunit of the adenosine monophosphate (AMP)-activated protein kinase gene.

Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.

We recently reported the hemochromatosis-like phenotype observed in our Usf2 knockout mice. In these mice, as in murine models of hemochromatosis and patients with hereditary hemochromatosis, iron accumulates in parenchymal cells (in particular, liver and pancreas), whereas the reticuloendothelial system is spared from this iron loading. We suggested that this phenotypic trait could be attributed to the absence, in the Usf2 knockout mice, of a secreted liver-specific peptide, hepcidin.

Bidirectional activity and orientation-dependent specificity of the rat aldolase C promoter in transgenic mice.

We previously reported that the rat aldolase C 115 bp promoter is sufficient to ensure the brain specific expression of the chloramphenicol acetyltransferase reporter gene in transgenic mice. We identify in a further reduced 84 bp promoter several putative binding sites for the transcriptional factors Sp1, USF, AP1, and AP2. Deletion or mutation of these partially overlapping binding sites results in inactivation of the cognate transgenes.