title: Stress-induced activation of the p53 tumor suppressor in leukemia cells and normal lymphocytes requires mitochondrial activity and reactive oxygen species.
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.
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Robert-Rossle-Clinic, HELIOS Klinikum Berlin-Buch, Charité Medical School, Berlin, Germany. karawajew@rrk.charite-buch.de <karawajew@rrk.charite-buch.de>
authors.forename: Leonid
authors.initials: L
authors.lastname: Karawajew
authors.forename: Peter
authors.initials: P
authors.lastname: Rhein
authors.forename: Grit
authors.initials: G
authors.lastname: Czerwony
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Ludwig
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004583:Electrons; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009840:Oligomycins / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D012402:Rotenone / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D002614:Chelating Agents; D009840:Oligomycins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D014475:Uncoupling Agents; D012402:Rotenone; D013804:Thenoyltrifluoroacetone; D005047:Etoposide; D000255:Adenosine Triphosphate; D010100:Oxygen