ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway

ETS2 is a transcription factor encoded by a gene on human chromosome 21 and alterations in its expression have been implicated in the pathophysiological features of Down syndrome (DS). This study demonstrates that overexpression of ETS2 results in apoptosis. This is shown in a number of circumstance...

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Bibliographic Details
Published in:Human molecular genetics 2003-02, Vol.12 (3), p.247-255
Main Authors: Wolvetang, E.J., Wilson, T.J., Sanij, E., Busciglio, J., Hatzistavrou, T., Seth, A., Hertzog, P.J., Kola, I.
Format: Article
Language:English
Subjects:
Ageing, cell death
Animals
Apoptosis - genetics
Apoptosis - physiology
Biological and medical sciences
Cell physiology
Chromosome aberrations
DNA-Binding Proteins
Down Syndrome - metabolism
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation - genetics
Gene Expression Regulation - physiology
HeLa Cells
Humans
Medical genetics
Medical sciences
Mice
Mice, Transgenic
Molecular and cellular biology
Proto-Oncogene Protein c-ets-2
Proto-Oncogene Proteins - biosynthesis
Proto-Oncogene Proteins - genetics
Repressor Proteins
Thymus Gland - pathology
Trans-Activators - biosynthesis
Trans-Activators - genetics
Transcription Factors
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - physiology
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Summary:ETS2 is a transcription factor encoded by a gene on human chromosome 21 and alterations in its expression have been implicated in the pathophysiological features of Down syndrome (DS). This study demonstrates that overexpression of ETS2 results in apoptosis. This is shown in a number of circumstances, including ETS2-overexpressing transgenic mice and cell lines and in cells from subjects with DS. Indeed we report for the first time that the ETS2 overexpression transgenic mouse develops a smaller thymus and lymphocyte abnormalities similar to that observed in DS. In all circumstances of ETS2 overexpression, the increased apoptosis correlated with increased p53 and alterations in downstream factors in the p53 pathway. In the human HeLa cancer cell line, transfection with functional p53 enables ETS2 overexpression to induce apoptosis. Furthermore, crossing the ETS2 transgenic mice with p53−/− mice genetically rescued the thymic apoptosis phenotype. Therefore, we conclude that overexpression of human chromosome 21-encoded ETS2 induces apoptosis that is dependent on p53. These results have important consequences for understanding DS and oncogenesis and may provide new insights into therapeutic interventions.
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/ddg015