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Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma.
- Source :
-
Cell [Cell] 2005 Nov 18; Vol. 123 (4), pp. 641-53. - Publication Year :
- 2005
-
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.
- Subjects :
- Animals
Apoptosis genetics
Apoptosis Regulatory Proteins genetics
Apoptosis Regulatory Proteins metabolism
Apoptosis Regulatory Proteins physiology
Bone Marrow radiation effects
Bone Marrow Transplantation
Cell Line, Transformed
Cell Line, Tumor
Chromatin Immunoprecipitation
Gamma Rays
Gene Expression genetics
Gene Expression radiation effects
Hematopoietic Stem Cells radiation effects
Humans
Introns genetics
Mice
Mice, Knockout
Mitochondria physiology
Mitochondria radiation effects
Models, Biological
Myeloid Progenitor Cells cytology
Myeloid Progenitor Cells metabolism
Myeloid Progenitor Cells radiation effects
Myelopoiesis radiation effects
Protein Binding genetics
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins c-bcl-2 metabolism
Snail Family Transcription Factors
Survival Analysis
Transcription Factors genetics
Transcription Factors metabolism
Transcriptional Activation genetics
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Tumor Suppressor Proteins metabolism
Apoptosis physiology
Hematopoietic Stem Cells physiology
Transcription Factors physiology
Tumor Suppressor Protein p53 physiology
Tumor Suppressor Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0092-8674
- Volume :
- 123
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 16286009
- Full Text :
- https://doi.org/10.1016/j.cell.2005.09.029