Abstract |
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.
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Authors | Leonid Karawajew, Peter Rhein, Grit Czerwony, Wolf-Dieter Ludwig |
Journal | Blood
(Blood)
Vol. 105
Issue 12
Pg. 4767-75
(Jun 15 2005)
ISSN: 0006-4971 [Print] United States |
PMID | 15705792
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chelating Agents
- Oligomycins
- Reactive Oxygen Species
- Tumor Suppressor Protein p53
- Uncoupling Agents
- Rotenone
- Thenoyltrifluoroacetone
- Etoposide
- Adenosine Triphosphate
- Oxygen
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Topics |
- Adenosine Triphosphate
(chemistry, metabolism)
- Apoptosis
- Cell Line, Tumor
- Cells, Cultured
- Chelating Agents
(pharmacology)
- Down-Regulation
- Drug Resistance, Neoplasm
- Electrons
- Etoposide
(pharmacology)
- Flow Cytometry
- Gene Expression Regulation, Neoplastic
- Genome
- Humans
- Intracellular Membranes
(metabolism)
- Lymphocytes
(metabolism)
- Membrane Potentials
- Mitochondria
(metabolism)
- Mutation
- Oligomycins
(pharmacology)
- Oligonucleotide Array Sequence Analysis
- Oxidative Stress
- Oxygen
(metabolism)
- Phosphorylation
- Reactive Oxygen Species
- Rotenone
(pharmacology)
- T-Lymphocytes
(metabolism)
- Thenoyltrifluoroacetone
(pharmacology)
- Time Factors
- Tumor Suppressor Protein p53
(metabolism)
- Uncoupling Agents
(pharmacology)
- Up-Regulation
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