Biomedical subjects
V Depraetere
Publications and source records attributed to V Depraetere.
PAR-1 helps Wnt to get rid of JNK.
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Getting activated with poly-ubiquitination.
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Origins of antigenic peptides.
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"Eat me" signals of apoptotic bodies.
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A dual function for RAD9.
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WW domain-containing FBP-30 is regulated by p53.
A subtractive cloning approach was used to clone genes transcriptionally induced in thymocytes undergoing programmed cell death after gamma-irradiation. We thus identified about 60 upregulated genes. One of these genes encodes a WW domain previously briefly reported by others, which defines this gene as FBP-30. cDNA sequencing showed FBP-30 to be remarkably conserved in mammals. FBP-30 expression, essentially restricted to T cells, was regulated by p53 since it increased (1) after gamma-irradiation in wild-type but not in p53-/- thymocytes and (2) in cells transfected with a conditional temperature-sensitive p53 mutant, less than 1 h after shifting to permissive temperature. Upregulation of FBP-30 expression thus depends upon p53 protein expression and correlates with cell death induction in these systems. While the kinetics of its induction are rapid, the observed increased expression of FBP-30 in the presence of protein synthesis inhibitors suggests that FBP-30 gene expression is indirectly regulated by p53, through downregulation of a labile inhibitor of FBP-30 expression.
Dismantling in cell death: molecular mechanisms and relationship to caspase activation.
The notion of a cell death programme was introduced in view of the reproducibility of its occurrence in time and space (e.g. in the developing embryo) and of its genetic determination. Programmed cell death can be schematically subdivided into three steps: a signalling phase, an execution phase and a dismantling phase. This review focuses on the latter. Apoptosis is the most studied form of dismantling of animal cells. The molecular pathways leading to certain apoptotic lesions appear to be dependent on the proteolytic activity of caspases. Death itself can, however, be caspase-independent. Also, non-apoptotic forms of cell death exist, even in animal cells; their molecular bases are still unknown. The relationship between cell death, apoptosis and caspases is discussed.
Fas and other cell death signaling pathways.
The Fas system ensures, within the immune system, one of the two main pathways of T-cell mediated cytotoxicity, and, importantly, at least part of the downregulation of immune responses. Recently, Fas has been increasingly implicated in other functions, such as protection of immune privileged tissues and disposal of cells undergoing genomic alterations. The Fas system can be viewed as a cell death signal, linking extracellular information to the cell death execution stage. In this review, the Fas pathway will be described, compared to the other known T-cell mediated cytotoxicity mechanism, and then more generally to other cell death signals. The general features of cell death signaling will be emphasized as well as the peculiarities of the Fas system.
Human thymic B cells largely overexpress the VH4 Ig gene family. A possible role in the control of tolerance in situ?
Human thymus contains a small population of B cells, a fraction of which expresses CD2 and/or CD5, as revealed by FACS analysis. Human thymic B cells enriched on CD19 panning revealed a constant co-expression of CD19 and Ig light chains. In the absence of detectable B precursors, these cells had reached at least the stage of IgM+ immature B lymphocytes. Analysis of Ig transcripts by PCR amplification first revealed a strong bias in favor of the VH4 and sequencing of 45 VH4-D-J cDNA clones isolated from two thymuses indicated that this thymic repertoire significantly differed from that of peripheral blood lymphocytes. Most genes of the VH4 family were used with various D-J combinations and a relatively high frequency of somatic mutations. This repertoire thus appears clearly selected in the thymus. This is of particular interest since the VH4 gene family is frequently encountered in autoimmunity a situation in which the number of thymic B cells is largely increased. They could play a major role in the control of tolerance in situ.
Homology between reaper and the cell death domains of Fas and TNFR1.
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TCR/CD3 coupling to Fas-based cytotoxicity.
We studied the coupling of the TCR/CD3 complex to a T cell effector function, namely Fas-based T-cell-mediated cytotoxicity. Encounter or re-encounter with antigen was mimicked by treating 5 d mixed lymphocyte culture cells or T cell hybridomas with anti-CD3 antibody. This TCR/CD3 engagement induced swift expression of Fas-based cytotoxicity in these cells. Induction of Fas-based cytotoxicity was Ca(2+)-dependent, while its execution was not; induction was sensitive to macromolecular synthesis inhibitors, in line with a demonstrable increase of the Fas ligand (Fas-L) message. We also used T cell hybridomas transfected with various constructs to dissect the involvement of distinct components of the TCR/CD3 complex. The cytoplasmic domain of the CD3 zeta chain was able to transduce by itself a signal leading to Fas-L expression, unless there were mutations in its activation receptor homology sequence 1 (ARH-1) motifs. On the one hand, these findings are relevant to signal transduction pathways coupled to the TCR/CD3, and on the other hand, to the involvement of Fas-based T cell-mediated cytotoxicity in various physiological and possibly pathophysiological situations.
Fas bridging cell death and cytotoxicity: the reaper connection.
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Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity.
Two molecular mechanisms of T cell-mediated cytotoxicity, one perforin-based, the other Fas-based, have been demonstrated. To determine the extent of their contribution to T cell-mediated cytotoxicity, a range of effector cells from normal control or perforin-deficient mice were tested against a panel of target cells with various levels of Fas expression. All cytotoxicity observed was due to either of these mechanisms, and no third mechanism was detected. Thus, the perforin- and Fas-based mechanisms may account for all T cell-mediated cytotoxicity in short-term in vitro assays.