SEARCH:   Advanced

Blood, 15 June 2005, Vol. 105, No. 12, pp. 4767-4775. Prepublished online as a Blood First Edition Paper on February 10, 2005; DOI 10.1182/blood-2004-09-3428. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-09-3428v1 105/12/4767    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Karawajew, L. Articles by Ludwig, W.-D. Search for Related Content PubMed PubMed Citation Articles by Karawajew, L. Articles by Ludwig, W.-D. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Stress-induced activation of the p53 tumor suppressor in leukemia cells and normal lymphocytes requires mitochondrial activity and reactive oxygen species Leonid Karawajew, Peter Rhein, Grit Czerwony, and Wolf-Dieter Ludwig From the Department of Hematology, Oncology, and Tumor Immunology, Robert-Rossle-Clinic at the HELIOS Klinikum Berlin-Buch, Charité Medical School, Berlin, Germany. The p53 system is highly stress sensitive and integrates diverse intracellular signals in a complex and poorly defined manner. We report on the high dependence of stress-induced p53 activation on mitochondrial activity. Down-regulation of mitochondrial transmembrane potential (MTMP) by inhibitors of electron transport (rotenone, thenoyltrifluoroacetone (TTFA)) and adenosine triphosphate (ATP) synthesis (oligomycin) prevented stress-induced p53 protein accumulation and abrogated p53-dependent apoptosis in a wild-type p53 leukemia cell line MOLT-3, in primary leukemia cells and in normal T lymphocytes. Using genome-wide gene expression analysis, stress-induced up-regulation of the p53 transcriptional targets and their specific inhibition by oligomycin has been demonstrated. Oligomycin did not impair p53-independent apoptosis and caused only a slight reduction of intracellular ATP levels. Reactive oxygen species (ROS) localized to mitochondria decreased in the presence of oligomycin, and stress-induced p53 activation showed strong ROS sensitivity both in leukemic and normal cells. These observations identify mitochondrial activity, described by MTMP and ROS levels, as a critical intracellular determinant of the p53 stress sensitivity and suggest potential implications of this linkage in the mechanisms of chemoresistance of acute leukemia cells. (Blood. 2005;105:4767-4775) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z. Derdak, N. M. Mark, G. Beldi, S. C. Robson, J. R. Wands, and G. Baffy The Mitochondrial Uncoupling Protein-2 Promotes Chemoresistance in Cancer Cells Cancer Res., April 15, 2008; 68(8): 2813 - 2819. [Abstract] [Full Text] [PDF] F. Meslin, J. Thiery, C. Richon, A. Jalil, and S. Chouaib Granzyme B-induced Cell Death Involves Induction of p53 Tumor Suppressor Gene and Its Activation in Tumor Target Cells J. Biol. Chem., November 9, 2007; 282(45): 32991 - 32999. [Abstract] [Full Text] [PDF] G. Santamaria, M. Martinez-Diez, I. Fabregat, and J. M. Cuezva Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase Carcinogenesis, May 1, 2006; 27(5): 925 - 935. [Abstract] [Full Text] [PDF] X. Zhou, J. D. Ferraris, and M. B. Burg Mitochondrial reactive oxygen species contribute to high NaCl-induced activation of the transcription factor TonEBP/OREBP Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1169 - F1176. [Abstract] [Full Text] [PDF]

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020