FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.
TL;DR: FoxO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment, a function that is required for its long-term regenerative potential.
About: This article is published in Cell.The article was published on 2007-01-26 and is currently open access. It has received 1511 citations till now. The article focuses on the topics: FOXO Family & Hematopoietic stem cell.
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TL;DR: It is argued that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
Abstract: Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
4,369 citations
Cites background from "FoxOs are critical mediators of hem..."
...The transcription factor Forkhead Box Os (FoxOs) was identified as a crucial factor to upregulate the expression of SOD and catalase, which confer resistance to oxidative stress and maintain stemness in this cell populatio...
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TL;DR: It is argued that redox biology, rather than oxidative stress, underlies physiological and pathological conditions.
4,297 citations
TL;DR: The pathways that regulate ROS homeostasis are crucial for mitigating the toxicity of ROS and provide strong evidence about specificity in ROS signalling.
Abstract: Reactive oxygen species (ROS) have been shown to be toxic but also function as signalling molecules. This biological paradox underlies mechanisms that are important for the integrity and fitness of living organisms and their ageing. The pathways that regulate ROS homeostasis are crucial for mitigating the toxicity of ROS and provide strong evidence about specificity in ROS signalling. By taking advantage of the chemistry of ROS, highly specific mechanisms have evolved that form the basis of oxidant scavenging and ROS signalling systems.
2,941 citations
Cites background from "FoxOs are critical mediators of hem..."
...This FOXO ROS-protective function is important for stem-cell surviva...
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TL;DR: Recent progress in understanding mTOR signaling is discussed, paying particular attention to its relevance in cancer and the use of rapamycin in oncology.
2,732 citations
Cites background from "FoxOs are critical mediators of hem..."
...genes develop thymic lymphomas and hemangiomas, unequivocally demonstrating that foxOs are tumor suppressors (Paik et al., 2007; Tothova et al., 2007)....
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...Mice deleted for the foxO1, foxO3, and foxO4 genes develop thymic lymphomas and hemangiomas, unequivocally demonstrating that foxOs are tumor suppressors (Paik et al., 2007; Tothova et al., 2007)....
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...Deletion of foxO1/3/4 in adult mouse hematopoietic cells results in a HSC defect phenotypically similar to the pten-deficient HSC model (Tothova et al., 2007)....
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TL;DR: The generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize are discussed, but also an outlook on their modulation in therapeutics is provided.
Abstract: Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumour development and progression. However, tumour cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signalling to effectively deprive cells from ROS-induced tumour promoting events, towards tipping the balance to ROS-induced apoptotic signalling. Alternatively, therapeutic antioxidants may prevent early events in tumour development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signalling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize, but also provides an outlook on their modulation in therapeutics.
2,625 citations
References
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TL;DR: The Gene Set Enrichment Analysis (GSEA) method as discussed by the authors focuses on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.
Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
34,830 citations
TL;DR: It is demonstrated that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors, which triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
6,481 citations
TL;DR: It is shown that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolongedRapamycin treatment reduces the levels of m TORC2 below those needed to maintain Akt/PKB signaling.
2,621 citations
"FoxOs are critical mediators of hem..." refers background in this paper
...The basis for the rapamycin effect in the Pten-deficient background is not clear, but it could be due to off-target effects of rapamycin that affect FoxO function, or differential effects of rapamycin on the mTORC1 versus mTORC2 complexes that influence AKT activity (Sarbassov et al., 2006)....
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TL;DR: The prospective identification, purification and characterization, using cell-surface markers and flow cytometry, of a complementary clonogenic common myeloid progenitor that gives rise to all myeloids lineages is reported.
Abstract: Haematopoietic stem cells give rise to progeny that progressively lose self-renewal capacity and become restricted to one lineage. The points at which haematopoietic stem cell-derived progenitors commit to each of the various lineages remain mostly unknown. We have identified a clonogenic common lymphoid progenitor that can differentiate into T, B and natural killer cells but not myeloid cells. Here we report the prospective identification, purification and characterization, using cell-surface markers and flow cytometry, of a complementary clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Common myeloid progenitors give rise to either megakaryocyte/erythrocyte or granulocyte/macrophage progenitors. Purified progenitors were used to provide a first-pass expression profile of various haematopoiesis-related genes. We propose that the common lymphoid progenitor and common myeloid progenitor populations reflect the earliest branch points between the lymphoid and myeloid lineages, and that the commitment of common myeloid progenitors to either the megakaryocyte/erythrocyte or the granulocyte/macrophage lineages are mutually exclusive events.
2,611 citations
"FoxOs are critical mediators of hem..." refers methods in this paper
...Flow Cytometry LSK, CMP, GMP, MEP, and CLP populations were analyzed and sorted with a FACSAria instrument (Becton Dickinson, Mountain View, CA) (Akashi et al., 2000; Kondo et al., 1997)....
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TL;DR: The Lin(-)IL-7R(+)Thy-1(-)Sca-1loc-Kit(lo) population from adult mouse bone marrow possessed a rapid lymphoid-restricted (T, B, and NK) reconstitution capacity in vivo but completely lacked myeloid differentiation potential either in vivo or in vitro.
2,296 citations
"FoxOs are critical mediators of hem..." refers methods in this paper
...Flow Cytometry LSK, CMP, GMP, MEP, and CLP populations were analyzed and sorted with a FACSAria instrument (Becton Dickinson, Mountain View, CA) (Akashi et al., 2000; Kondo et al., 1997)....
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