Transgenic expression of dominant negative tuberin through a strong constitutive promoter results in a tissue-specific tuberous sclerosis phenotype in the skin and brain
| Autor: | Emma Murad, Matthew Nunnelley, Toshiyuki Yamamoto, Francesca Cerimele, William D. Martin, Benjamin Lefkove, Baskaran Govindarajan, Karin Litani, Jack L. Arbiser, Marie Csete, Chunsik Lee, Daniel J. Brat, Cynthia Cohen |
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| Rok vydání: | 2004 |
| Předmět: |
Genetically modified mouse
Vascular Endothelial Growth Factor A Skin Neoplasms Receptors CCR2 Transgene Muscle Fibers Skeletal Apoptosis Mice Transgenic Biology Biochemistry Polymerase Chain Reaction Malignant transformation Tuberous sclerosis Mice Tuberous Sclerosis Tuberous Sclerosis Complex 2 Protein medicine Subependymal zone Animals RNA Messenger Transgenes Phosphorylation Promoter Regions Genetic Molecular Biology Alleles Chemokine CCL2 Genes Dominant Genetics Platelet-Derived Growth Factor Brain Neoplasms Ribosomal Protein S6 Kinases Tumor Suppressor Proteins Cell Biology medicine.disease Phenotype Molecular biology Repressor Proteins medicine.anatomical_structure Organ Specificity Mutation NIH 3T3 Cells Receptors Chemokine TSC1 TSC2 Reactive Oxygen Species |
| Zdroj: | The Journal of biological chemistry. 280(7) |
| ISSN: | 0021-9258 |
| Popis: | Tuberous sclerosis (TS) is a common autosomal dominant disorder caused by loss or malfunction of hamartin (tsc1) or tuberin (tsc2). Many lesions in TS do not demonstrate loss of heterozygosity for these genes, implying that dominant negative forms of these genes may account for some hamartomas and neoplasms in TS. To test this hypothesis, we expressed a dominant negative allele of tuberin (DeltaRG) behind the cytomegalovirus promoter in NIH3T3 cells and transgenic mice. This allele binds hamartin but has a deletion in the C terminus of tuberin, leading to constitutive activation of rap1 and rab5/rabaptin. Expression of DeltaRG in NIH3T3 cells led to a strong induction of reactive oxygen species, induction of vascular endothelial growth factor, and malignant transformation in vivo. Expression of DeltaRG driven by the constitutive cytomegalovirus promoter led to high level expression in all murine tissues examined, including skin, kidney, liver, and brain. Surprisingly, mice expressing the DeltaRG transgene developed a fibrovascular collagenoma in the dermis, which closely resembles the Shagreen patch observed in human patients with TS. In addition, numerous small subpial collections of external granule cells in the cerebellum were observed, which may be the murine equivalent of subependymal giant cell astrocytomas or tubers commonly seen in TS patients. Thus, expression of a dominant negative tuberin in multiple tissues can lead to a tissue-specific phenotype resembling some of the findings in human TS. Our data are the first to demonstrate that specific signaling abnormalities underlie specific hamartomas in a model of a human genetic disorder. |
| Databáze: | OpenAIRE |
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