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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Base Sequence, Cell Cycle, Cell Proliferation, DNA, Gene Expression Profiling, Genes, bcl-1, Hepatocytes, Liver, Liver Regeneration, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Models, Biological, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Signal Transduction, Transforming Growth Factor alpha, beta Catenin.
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Are the transforming growth factor-α and cyclin D1 genes direct targets of β-catenin signaling in hepatocyte proliferation? Context: β-Catenin is an oncogene frequently mutated in hepatocellular carcinoma. In this study, we investigated target genes of β-catenin signaling in hepatocyte proliferation. We studied transgenic mice displaying either inactivation or activation of the β-catenin pathway, focusing on analysis of liver proliferation due to aberrant β-catenin activation, and on the regeneration process during which β-catenin signaling is transiently activated. We localized in situ the various partners involved in proliferation or identified as targets of β-catenin in these transgenic and regenerating livers. We also performed comparative transcriptome analyses, using microarrays. Finally, we extracted, from deep-sequencing data, both the DNA regulatory elements bound to the β-catenin/Tcf nuclear complex and the expression levels of critical targets identified in microarrays. β-Catenin activation during liver regeneration occurred during G1/S cell cycle progression and allowed zonal extension of the normal territory of active β-catenin and panlobular proliferation. We found that β-catenin controlled both cell-autonomous and non-cell-autonomous hepatocyte proliferation, through direct transcriptional and complex control of cyclin D1 gene expression and of the expression of a new target gene, Tgfα.
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We propose that β-catenin controls panlobular hepatocyte proliferation partly by controlling, together with its Tcf4 nuclear partner, expression of the pro-proliferation cyclin D1 and Tgfα genes. This study constitutes a first step toward understanding the oncogenic properties of this prominent signaling pathway in the liver. Final Decision: yes