This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Micali, N.
Right arrow Articles by Crippa, M. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Micali, N.
Right arrow Articles by Crippa, M. P.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2009, p. 1143-1151, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01273-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Prep1 Directly Regulates the Intrinsic Apoptotic Pathway by Controlling Bcl-XL Levels{triangledown} ,{dagger}

Nicola Micali,1 Carmelo Ferrai,1 Luis C. Fernandez-Diaz,2 Francesco Blasi,1,2,3* and Massimo P. Crippa1*

Laboratory of Molecular Genetics, S. Raffaele Scientific Institute, Milan, Italy,1 IFOM (FIRC Institute of Molecular Oncology), Milan, Italy,2 School of Medicine, Università Vita-Salute S. Raffaele, Milan, Italy3

Received 11 August 2008/ Returned for modification 22 October 2008/ Accepted 14 December 2008

The Prep1 homeodomain transcription factor is essential in embryonic development. Prep1 hypomorphic mutant mouse (Prep1i/i) embryos (embryonic day 9.5) display an increased terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling reaction compared to wild-type (WT) littermates. Prep1i/i mouse embryo fibroblasts (MEFs) show an increased basal level of annexin V binding activity, reduction of the mitochondrial-membrane potential, and increased caspase 9 and 3 activation, indicating increased apoptosis. Prep1i/i MEFs also respond faster than WT MEFs to genotoxic stress, indicating increased activation of the intrinsic apoptotic pathways. We did not observe an increase in p53 or an abnormal p53 response to apoptotic stimuli. However, hypomorphic MEFs have decreased endogenous levels of antiapoptotic Bcl-XL mRNA and protein, and Bcl-x overexpression rescues the defect of Prep1i/i MEFs. Using transient transfections and chromatin immunoprecipitation, we identified the Bcl-x promoter as a novel target of Prep1. Thus, Prep1 directly controls mitochondrial homeostasis (and the apoptotic potential) by modulating Bcl-x gene expression.

* Corresponding author. Mailing address for Massimo P. Crippa: Laboratory of Molecular Genetics, DiBiT, S. Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Phone: 39 02 2643 4833. Fax: 39 02 2643 4844. E-mail: crippa.massimo{at}hsr.it. Mailing address for Francesco Blasi: Università Vita Salute San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Phone: 39 02 2643 4744. Fax: 39 02 2643 4844. E-mail: blasi.francesco{at}hsr.it

{triangledown} Published ahead of print on 22 December 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, March 2009, p. 1143-1151, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01273-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Micali, N., Longobardi, E., Iotti, G., Ferrai, C., Castagnaro, L., Ricciardi, M., Blasi, F., Crippa, M. P. (2010). Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress. Nucleic Acids Res : gkq019v1-gkq019 [Abstract] [Full Text]  
  • Nowick, K., Gernat, T., Almaas, E., Stubbs, L. (2009). Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain. Proc. Natl. Acad. Sci. USA 106: 22358-22363 [Abstract] [Full Text]  
  • Castellano, L., Giamas, G., Jacob, J., Coombes, R. C., Lucchesi, W., Thiruchelvam, P., Barton, G., Jiao, L. R., Wait, R., Waxman, J., Hannon, G. J., Stebbing, J. (2009). The estrogen receptor-{alpha}-induced microRNA signature regulates itself and its transcriptional response. Proc. Natl. Acad. Sci. USA 106: 15732-15737 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»