Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains
| Autor: | Grégory Bellot, Danièle Roux, Raquel Garcia-Medina, Nathalie M. Mazure, Johanna Chiche, Jacques Pouysségur, Pierre Gounon |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Programmed cell death
Molecular Sequence Data Biology Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Proto-Oncogene Proteins Autophagy Basic Helix-Loop-Helix Transcription Factors medicine Animals Humans Gene silencing Amino Acid Sequence RNA Small Interfering Molecular Biology 030304 developmental biology Mice Knockout 0303 health sciences Tumor Suppressor Proteins Membrane Proteins Articles Cell Biology Fibroblasts Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Cell Hypoxia Peptide Fragments Protein Structure Tertiary Cell biology Gene Expression Regulation Hypoxia-inducible factors Cell culture Tumor progression 030220 oncology & carcinogenesis Beclin-1 Ectopic expression medicine.symptom Apoptosis Regulatory Proteins Sequence Alignment |
| Zdroj: | Molecular and Cellular Biology. 29:2570-2581 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00166-09 |
| Popis: | While hypoxia-inducible factor (HIF) is a major actor in the cell survival response to hypoxia, HIF also is associated with cell death. Several studies implicate the HIF-induced putative BH3-only proapoptotic genes bnip3 and bnip3l in hypoxia-mediated cell death. We, like others, do not support this assertion. Here, we clearly demonstrate that the hypoxic microenvironment contributes to survival rather than cell death by inducing autophagy. The ablation of Beclin1, a major actor of autophagy, enhances cell death under hypoxic conditions. In addition, the ablation of BNIP3 and/or BNIP3L triggers cell death, and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. First, while the small interfering RNA-mediated ablation of either BNIP3 or BNIP3L has little effect on autophagy, the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy. Second, the ectopic expression of both BNIP3 and BNIP3L in normoxia activates autophagy. Third, 20-mer BH3 peptides of BNIP3 or BNIP3L are sufficient in initiating autophagy in normoxia. Herein, we propose a model in which the atypical BH3 domains of hypoxia-induced BNIP3/BNIP3L have been designed to induce autophagy by disrupting the Bcl-2-Beclin1 complex without inducing cell death. Hypoxia-induced autophagy via BNIP3 and BNIP3L is clearly a survival mechanism that promotes tumor progression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|