Home About us Contact
|
Home About us Contact | ||
|
|
||
Appropriate Signal (appropriate + signal)
Selected AbstractsStem cell generation and choice of fate: role of cytokines and cellular microenvironmentJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 4 2000S.N. Constantinescu Hematopoietic stem cells (HSC) have provided a model for the isolation, enrichment and transplantation of stem cells. Gene targeting studies in mice have shown that expression of the thrombopoietin receptor (TpoR) is linked to the accumulation of HSCs capable to generate long-term blood repopulation when injected into irradiated mice. The powerful increase in vivo in HSC numbers by retrovirally transduced HOX4B, a homeotic gene, along with the role of the TpoR, suggested that stem cell fate, renewal, differentiation and number can be controlled. The discovery of the precise region of the mouse embryo where HSCs originate and the isolation of supporting stromal cell lines open the possibility of identifying the precise signals required for HSC choice of fate. The completion of human genome sequencing coupled with advances in gene expression profiling using DNA microarrays will enable the identification of key genes deciding the fate of stem cells. Downstream from HSCs, multipotent hematopoietic progenitor cells appear to co-express a multiplicity of genes characteristic of different blood lineages. Genomic approaches will permit the identification of the select group of genes consolidated by the commitment of these multipotent progenitors towards one or the other of the blood lineages. Studies with neural stem cells pointed to the unexpected plastic nature of these cells. Isolation of stem cells from multiple tissues may suggest that, providing the appropriate environment/signal, tissues could be regenerated in the laboratory and used for transplantation. A spectacular example of influence of the environment on cell fate was revealed decades ago by using mouse embryonic stem cells (ES). Injected into blastocysts, ES cells contribute to the formation of all adult tissues. Injected into adult mice, ES cells become cancer cells. After multiple passages as ascites, when injected back into the blastocyst environment, ES- derived cancer cells behaved again as ES cells. More recently, the successful cloning of mammals and reprogramming of transferred nuclei by factors in the cytoplasm of oocytes turned back the clock by showing that differentiated nuclei can be "re-booted" to generate again the stem cells for different tissues. [source] Structure of the human p53 core domain in the absence of DNAACTA CRYSTALLOGRAPHICA SECTION D, Issue 3 2007Ying Wang The tumor suppressor protein p53 plays a key role in cell-cycle regulation by triggering DNA repair, cell-cycle arrest and apoptosis when the appropriate signal is received. p53 has the classic architecture of a transcription factor, with an amino-terminal transactivation domain, a core DNA-binding domain and carboxy-terminal tetramerization and regulatory domains. The crystal structure of the p53 core domain, which includes the amino acids from residue 96 to residue 289, has been determined in the absence of DNA to a resolution of 2.05,Å. Crystals grew in a new monoclinic space group (P21), with unit-cell parameters a = 68.91, b = 69.36, c = 84.18,Å, , = 90.11°. The structure was solved by molecular replacement and has been refined to a final R factor of 20.9% (Rfree = 24.6%). The final model contains four molecules in the asymmetric unit with four zinc ions and 389 water molecules. The non-crystallographic tetramers display different protein contacts from those in other p53 crystals, giving rise to the question of how p53 arranges as a tetramer when it binds its target DNA. [source] Either interleukin-12 or interferon-, can correct the dendritic cell defect induced by transforming growth factor ,1 in patients with myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2004Ross Brown Summary The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44+) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up-regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor ,1 (TGF,1) and interleukin (IL)-10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti-TGF,1. As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up-regulation was reduced in both stage I and stage III. It was demonstrated that both IL-12 and interferon- , neutralized the failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123,) suggesting that there would be a predominantly T-helper cell type response. The addition of IL-12 or interferon- , to future immunotherapy trials involving these patients should be considered. [source] Cell kinetic studies in murine ventral tongue epithelium: cell cycle progression studies using double labelling techniquesCELL PROLIFERATION, Issue 2002C. S. Potten Abstract. The dorsal and ventral epithelia on the murine tongue exhibit very pronounced circadian rhythms in terms of the cell cycle. These rhythms are such that three injections of tritiated thymidine 3 h apart spanning the circadian peak in S phase cells labelled between 40 and 50% of the basal cells. Injection of bromodeoxyuridine generally gave slightly lower labelling indices. Approximately the same proportion (54% of the basal cells) could be accumulated in metaphase over a 24-h period using vincristine as a stathmokinetic agent. The experiments reported here using mouse ventral tongue epithelium use double-labelling approaches to address the question: what proportion of the approximately 50% of the basal cells that are proliferating have a 24-h cell cycle and can therefore be labelled by a similar labelling protocol the following day? The results suggest a heterogeneity amongst the proliferating basal cells, similar to the heterogeneity proposed for the dorsal tongue epithelium. Although not all the basal component has been accounted for, the data presented here suggest that about 20% of the basal cells may have a cell cycle time of 24 h, about 30% appear to have a longer cell cycle time (48 or 72 h), while about 20% of the basal cells appear to be postmitotic maturing G1 cells, awaiting the appropriate signals for migration into the suprabasal layer. [source] Signalling and phagocytosis in the orchestration of host defenceCELLULAR MICROBIOLOGY, Issue 2 2007J. Magarian Blander Summary Dendritic cells (DCs) orchestrate either tolerance or immunity. At the heart of this function lies phagocytosis, which allows DCs to sample the tissue microenvironment and deliver both its self and non-self constituents into endocytic compartments for clearance, degradation and presentation by major histocompatibility complex (MHC) molecules. Depending on the type of signalling pathways triggered during phagocytosis, DCs deliver appropriate signals to T cells that determine either their tolerance or activation and differentiation. Here I draw attention to the ability of DCs to read the contents of their phagosomes depending on the type of compartmentalized signalling pathways engaged during internalization. Toll-like receptors (TLRs) engaged during phagocytosis of microbial pathogens, but not syngeneic apoptotic cells exert phagosome autonomous control on both the kinetics and outcome of phagosome maturation. By bearing the assembly of signalling complexes on their membranes, individual phagosomes undergo separate programmes of maturation irrespective of the activation status of the DC carrying them. Phagosomes carrying microbial cargo are favoured for MHC class II presentation precluding phagosomes carrying self from contributing to the first signal delivered to T cells , the peptide,MHC complex. This mechanism prevents the potential presentation of peptides derived from self within the context of TLR-induced co-stimulatory signals. [source] | |||||||||||||