Downregulation of hepatocyte nuclear factor-4α and its role in regulation of gene expression by TGF-β in mammary epithelial cells
| Autor: | Motoko Shibanuma, Fumihiro Ishikawa, Kiyoshi Nose |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Gene isoform
Molecular Sequence Data Receptor Transforming Growth Factor-beta Type I Down-Regulation SMAD Protein Serine-Threonine Kinases Cycloheximide digestive system Transforming Growth Factor beta1 Mice chemistry.chemical_compound Mammary Glands Animal Downregulation and upregulation Animals Humans Protein Isoforms Smad3 Protein Psychological repression Cells Cultured Oligonucleotide Array Sequence Analysis Regulation of gene expression biology Gene Expression Profiling HMGA2 Protein Tenascin C Epithelial Cells Cell Biology Hepatocyte nuclear factors Cell Transformation Neoplastic Retroviridae Gene Expression Regulation Hepatocyte Nuclear Factor 4 chemistry embryonic structures biology.protein Cancer research Female Receptors Transforming Growth Factor beta Signal Transduction |
| Zdroj: | Experimental Cell Research. 314:2131-2140 |
| ISSN: | 0014-4827 |
| DOI: | 10.1016/j.yexcr.2008.03.013 |
| Popis: | We found that a specific isoform of hepatocyte nuclear factor 4alpha (HNF-4alpha), HNF-4alpha8, was expressed in mouse mammary epithelial NMuMG cells, and that its expression was repressed by TGF-beta. The repression was interfered by dominant negative forms of activin receptor-like kinase 5 (ALK5) and Smad3, and sensitive to cycloheximide, suggesting the involvement of additional protein(s) as well as ALK5 and Smad3 in the repression. Further study showed that high mobility group A2 (HMGA2), which is reported to be directly upregulated by Smads, repressed HNF-4alpha8 expression. Therefore, it is likely that HMGA2 mediates the downregulation of HNF-4alpha8 downstream of ALK5 and Smads To determine the significance of the downregulation of HNF-4alpha8 in TGF-beta signaling, we performed DNA microarray analysis and extracted a subgroup of TGF-beta1-regulated genes, including tenascin C and tissue inhibitor of metalloproteinase 3 (TIMP-3), whose regulation by TGF-beta1 was attenuated by forced expression of HNF-4alpha8. HMGA2 has recently emerged as a transcriptional organizer of TGF-beta signaling, regulating several key factors involved in epithelial-mesenchymal transition (EMT). In this study, we identified an isoform of HNF-4alpha as a new target downstream of HMGA2 and assigned a new role to HNF-4alpha in the TGF-beta signaling/transcriptional cascade driven by ALK5/Smad/HMGA2 and associated with the malignant transformation of cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect