Human Molecular Genetics, 2003, Vol. 12, No. 3 247-255
© 2003 Oxford University Press
ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway
1Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria, Australia, 2Department of Neuroscience MC-3401, University of Connecticut Health Center, Farmington, CT 06030, USA and 3Department of Pathology, Faculty of Medicine and Faculty of Dentistry, University of Toronto and Women's College Hospital, Toronto, Ontario, Canada
Received September 13, 2002; Accepted November 13, 2002
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.
* To whom correspondence should be addressed at: Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, 246 Clayton Road, Clayton, VIC 3168, Australia. Tel: 613 95947202; Fax: 613 95947221; Email: paul.hertzog{at}med.monash.edu.au
Present address: Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, MI 49007, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Malinge, S. Izraeli, and J. D. Crispino Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome Blood, March 19, 2009; 113(12): 2619 - 2628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Segditsas, O. Sieber, M. Deheragoda, P. East, A. Rowan, R. Jeffery, E. Nye, S. Clark, B. Spencer-Dene, G. Stamp, et al. Putative direct and indirect Wnt targets identified through consistent gene expression changes in APC-mutant intestinal adenomas from humans and mice Hum. Mol. Genet., December 15, 2008; 17(24): 3864 - 3875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Lapaire, D. W. Bianchi, I. Peter, B. O'Brien, H. Stroh, J. M. Cowan, U. Tantravahi, and K. L. Johnson Cell-Free Fetal DNA in Amniotic Fluid: Unique Fragmentation Signatures in Euploid and Aneuploid Fetuses Clin. Chem., March 1, 2007; 53(3): 405 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Luco, M. A. Maestro, N. del Pozo, W. M. Philbrick, P. P. de la Ossa, and J. Ferrer A Conditional Model Reveals That Induction of Hepatocyte Nuclear Factor-1{alpha} in Hnf1{alpha}-Null Mutant {beta}-Cells Can Activate Silenced Genes Postnatally, Whereas Overexpression Is Deleterious. Diabetes, August 1, 2006; 55(8): 2202 - 2211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Helguera, A. Pelsman, G. Pigino, E. Wolvetang, E. Head, and J. Busciglio ets-2 Promotes the Activation of a Mitochondrial Death Pathway in Down's Syndrome Neurons J. Neurosci., March 2, 2005; 25(9): 2295 - 2303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Prescott, K. S. N. Koto, M. Singh, and A. Gutierrez-Hartmann The ETS Transcription Factor ESE-1 Transforms MCF-12A Human Mammary Epithelial Cells via a Novel Cytoplasmic Mechanism Mol. Cell. Biol., June 15, 2004; 24(12): 5548 - 5564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Baldus, S. Liyanarachchi, K. Mrozek, H. Auer, S. M. Tanner, M. Guimond, A. S. Ruppert, N. Mohamed, R. V. Davuluri, M. A. Caligiuri, et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes PNAS, March 16, 2004; 101(11): 3915 - 3920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. G. Saran, M. T. Pletcher, J. E. Natale, Y. Cheng, and R. H. Reeves Global disruption of the cerebellar transcriptome in a Down syndrome mouse model Hum. Mol. Genet., August 15, 2003; 12(16): 2013 - 2019. [Abstract] [Full Text] [PDF]
|
|