Molecular cell, 2007-11, Vol.28 (4), p.624-637
2007
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Nonapoptotic Role for Apaf-1 in the DNA Damage Checkpoint
- Ist Teil von
- Molecular cell, 2007-11, Vol.28 (4), p.624-637
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2007
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Apaf-1 is an essential factor for cytochrome c-driven caspase activation during mitochondrial apoptosis but has also an apoptosis-unrelated function. Knockdown of Apaf-1 in human cells, knockout of apaf-1 in mice, and loss-of-function mutations in the Caenorhabditis elegans apaf-1 homolog ced-4 reveal the implication of Apaf-1/CED-4 in DNA damage-induced cell-cycle arrest. Apaf-1 loss compromised the DNA damage checkpoints elicited by ionizing irradiation or chemotherapy. Apaf-1 depletion reduced the activation of the checkpoint kinase Chk1 provoked by DNA damage, and knockdown of Chk1 abrogated the Apaf-1-mediated cell-cycle arrest. Nuclear translocation of Apaf-1, induced in vitro by exogenous DNA-damaging agents, correlated in non-small cell lung cancer (NSCLC) with the endogenous activation of Chk-1, suggesting that this pathway is clinically relevant. Hence, Apaf-1 exerts two distinct, phylogenetically conserved roles in response to mitochondrial membrane permeabilization and DNA damage. These data point to a role for Apaf-1 as a bona fide tumor suppressor.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1097-2765eISSN: 1097-4164DOI: 10.1016/j.molcel.2007.09.030Titel-ID: cdi_proquest_miscellaneous_68548596
- Format
- –
- Schlagworte
- Animals, Apoptosis - drug effects, Apoptotic Protease-Activating Factor 1 - deficiency, Apoptotic Protease-Activating Factor 1 - metabolism, Caenorhabditis elegans - cytology, Caenorhabditis elegans - drug effects, Caenorhabditis elegans - metabolism, Caenorhabditis elegans Proteins - metabolism, Calcium-Binding Proteins - metabolism, Carcinoma, Non-Small-Cell Lung - enzymology, Cell Cycle - drug effects, Cell Line, Tumor, Cell Nucleus - metabolism, CELLCYCLE, Checkpoint Kinase 1, Cisplatin - pharmacology, Conserved Sequence, DNA Damage, Embryo, Mammalian - cytology, Embryo, Mammalian - drug effects, Embryo, Mammalian - metabolism, Humans, Lung Neoplasms - enzymology, Mice, Phosphorylation - drug effects, Phylogeny, Protein Kinases - metabolism, Protein Transport - drug effects