Extracellular adenosine sensing-a metabolic cell death priming mechanism downstream of p53
| Autor: | Diane Crighton, Timothy M. Palmer, Kevin M. Ryan, Jaclyn S. Long, Eyal Gottlieb, James O'Prey, Gillian M. Mackay, Liang Zheng |
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| Rok vydání: | 2012 |
| Předmět: |
Programmed cell death
Adenosine Cell Survival Down-Regulation Apoptosis Receptor Adenosine A2B Mice Downregulation and upregulation Cell Line Tumor Extracellular medicine Animals Humans Viability assay Hypoxia Molecular Biology Caspase biology Cell Death Cell Biology Purinergic signalling HCT116 Cells Cell biology Up-Regulation Mice Inbred C57BL Proto-Oncogene Proteins c-bcl-2 Caspases biology.protein Tumor Suppressor Protein p53 Apoptosis Regulatory Proteins medicine.drug |
| Zdroj: | Molecular cell. 50(3) |
| ISSN: | 1097-4164 |
| Popis: | Tumor cells undergo changes in metabolism to meet their energetic and anabolic needs. It is conceivable that mechanisms exist to sense these changes and link them to pathways that eradicate cells primed for cancer development. We report that the tumor suppressor p53 activates a cell death priming mechanism that senses extracellular adenosine. Adenosine, the backbone of ATP, accumulates under conditions of cellular stress or altered metabolism. We show that its receptor, A2B, is upregulated by p53. A2B expression has little effect on cell viability, but ligand engagement activates a caspase- and Puma-dependent apoptotic response involving downregulation of antiapoptotic Bcl-2 proteins. Stimulation of A2B also significantly enhances cell death mediated by p53 and upon accumulation of endogenous adenosine following chemotherapeutic drug treatment and exposure to hypoxia. Since extracellular adenosine also accumulates within many solid tumors, this distinct p53 function links programmed cell death to both a cancer- and therapy-associated metabolic change. |
| Databáze: | OpenAIRE |
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