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Khanna, KK; Lavin, MF; Jackson, SP; Mulhern, TD
doi: 10.1038/sj.cdd.4400874pmid: 11687884
Mutations in the ATM gene lead to the genetic disorder ataxia-telangiectasia. ATM encodes a protein kinase that is mainly distributed in the nucleus of proliferating cells. Recent studies reveal that ATM regulates multiple cell cycle checkpoints by phosphorylating different targets at different stages of the cell cycle. ATM also functions in the regulation of DNA repair and apoptosis, suggesting that it is a central regulator of responses to DNA double-strand breaks. Cell Death and Differentiation (2001) 8, 1052–1065
doi: 10.1038/sj.cdd.4400943pmid: 11687885
Knowledge of the emerging pathways of cell death downstream of the p53 tumor suppressor and the TRAIL death-inducing ligand is suggesting ways to improve therapeutic design in cancer. In contrast to its unique G1 cell cycle arresting mechanism that is maintained by p21WAF1, there are signals transduced by p53 to multiple apoptotic effectors perhaps due to the importance of apoptosis in suppressing tumors. There is evidence for cytoplasmic as well as mitochondrial activation of caspases downstream of p53, although in some cell lineages the signal ultimately involves the mitochondria. The TRAIL signaling pathway appears promising for therapeutic development despite sharing some similarities with the toxic Fas and TNF pathways, in terms of effector molecules and downstream signals. One of the key findings is the tissue specificity of cell death responses, a feature that could be exploited in strategies to widen the therapeutic window of combination cancer therapies. Efforts continue to develop p53-targeted cancer therapy, and novel clues to enhance or block specific effectors may improve therapeutic design. Cell Death and Differentiation (2001) 8, 1066–1075
doi: 10.1038/sj.cdd.4400948pmid: 11687886
The mismatch repair (MMR) system promotes genomic fidelity by repairing base-base mismatches, insertion-deletion loops and heterologies generated during DNA replication and recombination. This function is critically dependent on the assembling of multimeric complexes involved in mismatch recognition and signal transduction to downstream repair events. In addition, MMR proteins coordinate a complex network of physical and functional interactions that mediate other DNA transactions, such as transcription-coupled repair, base excision repair and recombination. MMR proteins are also involved in activation of cell cycle checkpoint and induction of apoptosis when DNA damage overwhelms a critical threshold. For this reason, they play a role in cell death by alkylating agents and other chemotherapeutic drugs, including cisplatin. Inactivation of MMR genes in hereditary and sporadic cancer is associated with a mutator phenotype and inhibition of apoptosis. In the future, a deeper understanding of the molecular mechanisms and functional interactions of MMR proteins will lead to the development of more effective cancer prevention and treatment strategies. Cell Death and Differentiation (2001) 8, 1076–1092
Lee, S-Y; Song, E J; Kim, H-J; Kang, H-J; Kim, J-H; Lee, K-J
doi: 10.1038/sj.cdd.4400923pmid: 11687887
Rac1 has been implicated in a wide variety of biological processes, including actin remodeling and various signaling cascades. Here we have examined whether Rac1 might be involved in heat shock-induced cell signaling. We found that Rat2 stable cells expressing a dominant negative Rac1 mutant, RacN17 (Rat2-RacN17), were significantly more tolerant to heat shock than control Rat2 cells, and simultaneously inhibited the activation of SAPK/JNK by heat shock compared to control Rat2 cells. However, no discernible effect was observed in typical heat shock responses including total protein synthesis and heat shock protein synthesis. To identify the proteins involved in this difference, we separated the proteins of both Rat2 and Rat2-RacN17 cell lines after heat shock using two-dimensional gel electrophoresis and identified the differentially expressed proteins by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) after in-gel trypsin digestion. Differentially expressed proteins between two cell lines were identified as vimentin. Rat2-RacN17 cells showed significant changes in vimentin as well as marked changes in vimentin reorganization by heat shock. The vimentin changes were identified as N-terminal head domain cleavage. These results suggest that Rac1 plays a pivotal role in the heat shock-induced signaling cascade by modifying intermediate vimentin filaments. Cell Death and Differentiation (2001) 8, 1093–1102
Philippoussis, F; Przybytkowski, E; Fortin, M; Arguin, C; Pande, SV; Steff, A-M; Hugo, P
doi: 10.1038/sj.cdd.4400917pmid: 11687888
Recently, lipids have received considerable attention for their potential to induce apoptosis when added exogenously to cells. In this study, we directly demonstrate that murine T-cells undergo rapid apoptosis following treatment with various forms of monoglycerides, which are a family of naturally occurring lipids consisting of a single fatty acid moiety attached to a glycerol backbone. The potency of these lipids varied depending on their chemical structure, whereas glycerol backbone or corresponding fatty acids alone were ineffective. Moreover, monoglyceride-mediated apoptosis was suppressed either by Bcl-2 overexpression, treatment with a broad inhibitor of caspases, or RNA and protein synthesis inhibitors. In addition, treatment of cells with derivatives of monoglycerides induced a calcium flux, which could be inhibited by both extracellular (EGTA) or intracellular (EGTA-AM) calcium chelators. To our knowledge, this is the first report demonstrating a role for derivatives of monoglycerides as inducers of apoptosis in mammalian cells. Cell Death and Differentiation (2001) 8, 1103–1112
Fujii, C; Shiratsuchi, A; Manaka, J; Yonehara, S; Nakanishi, Y
doi: 10.1038/sj.cdd.4400920pmid: 11687889
Dying cells are selectively eliminated from the organism by phagocytosis. Previous studies suggested the existence of some other phagocytosis marker(s) that function together with phosphatidylserine, the best-characterized phagocytosis marker. We obtained here a monoclonal antibody named PH2 that inhibited macrophage phagocytosis of late apoptotic or necrotic cells, but not of early apoptotic cells. On the other hand, phagocytosis of cells at any time during the process of apoptosis was inhibitable by phosphatidylserine-containing liposomes. Inhibition occurred even when target cells were preincubated with PH2 and separated from unbound antibodies. Moreover, PH2 bound to apoptotic cells at late stages more efficiently than to those at early stages, and it did not bind to normal cells unless their plasma membrane was permeabilized. These results suggest that the putative PH2 antigen is a novel phagocytosis marker that translocates to the cell surface at late stages of apoptosis, resulting in maximal recognition and engulfment by macrophages. Cell Death and Differentiation (2001) 8, 1113–1122
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