Abstract
In response to DNA damage, the p53 tumor suppressor can elicit either apoptosis or cell-cycle arrest and repair, but how this critical decision is made in specific cell types remains largely undefined. We investigated the mechanism by which the transcriptional repressor Slug specifically rescues hematopoietic progenitor cells from lethal doses of gamma radiation. We show that Slug is transcriptionally induced by p53 upon irradiation and then protects the damaged cell from apoptosis by directly repressing p53-mediated transcription of puma, a key BH3-only antagonist of the antiapoptotic Bcl-2 proteins. We established the physiologic significance of Slug-mediated repression of puma by demonstrating that mice deficient in both genes survive doses of total-body irradiation that lethally deplete hematopoietic progenitor populations in mice lacking only slug. Thus, Slug functions downstream of p53 in developing blood cells as a critical switch that prevents their apoptosis by antagonizing the trans-activation of puma by p53.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis Regulatory Proteins / physiology
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Bone Marrow / radiation effects
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Bone Marrow Transplantation
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Cell Line, Transformed
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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Gamma Rays
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Gene Expression / genetics
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Gene Expression / radiation effects
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Hematopoietic Stem Cells / physiology*
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Hematopoietic Stem Cells / radiation effects
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Humans
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Introns / genetics
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Mice
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Mice, Knockout
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Mitochondria / physiology
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Mitochondria / radiation effects
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Models, Biological
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Myeloid Progenitor Cells / cytology
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Myeloid Progenitor Cells / metabolism
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Myeloid Progenitor Cells / radiation effects
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Myelopoiesis / radiation effects
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Protein Binding / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Snail Family Transcription Factors
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Survival Analysis
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcriptional Activation / genetics
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Protein p53 / physiology*
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
Substances
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Apoptosis Regulatory Proteins
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PUMA protein, mouse
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Pmaip1 protein, mouse
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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SNAI1 protein, human
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Snai2 protein, mouse
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Snail Family Transcription Factors
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Bcl2 protein, mouse