Abstract
Although the p53 tumor suppressor/transcription factor often accumulates in the cytoplasm of healthy cells, limited information is available on the cytoplasmic function of p53. Here, we show that cytoplasmic p53 suppresses cell invasion by reducing mitochondrial reactive oxygen species (ROS) levels. Analysis revealed that this function is mediated by Bcl-2 family proteins: Cytoplasmic p53 binds Bcl-w, liberating Bax, which then binds ND5, a subunit of respiratory complex-I, thereby suppressing complex-I activity and thus ROS production. The G13289A mutation of ND5, identified in cancer patients, prevents Bax/ND5 interactions and promotes ROS production and cell invasion. We also showed that Bcl-XL and Bak can substitute for Bcl-w and Bax, respectively, regulating complex-I activity and supporting the cytoplasmic function of p53; nuclear p53 also suppresses complex-I activity by inducing Bax expression. Studies in animal models support the notion that p53 and Bcl-2 family proteins exhibit these functions in vivo. This study demonstrates a link between p53 and Bcl-2 proteins as regulators of ROS production and cellular invasiveness, and reveals complex-I, especially ND5, as their functional target.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / metabolism
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Cell Line, Tumor
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Cell Movement*
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Cell Nucleus / metabolism*
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Cytoplasm / metabolism*
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Electron Transport Complex I / genetics
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Electron Transport Complex I / metabolism*
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Female
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Mice, Inbred BALB C
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Mice, Nude
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Mitochondria / metabolism
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Mutation
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Neoplasm Invasiveness
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Protein Binding
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Protein Interaction Domains and Motifs
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA Interference
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Reactive Oxygen Species / metabolism
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Signal Transduction
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Time Factors
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Transfection
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Tumor Burden
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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BAX protein, human
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BCL2L1 protein, human
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BCL2L2 protein, human
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Mitochondrial Proteins
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Proto-Oncogene Proteins c-bcl-2
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Reactive Oxygen Species
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TP53 protein, human
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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bcl-X Protein
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MT-ND5 protein, human
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Electron Transport Complex I