The extracellular matrix, p53 and estrogen compete to regulate cell-surface Fas/Apo-1 suicide receptor expression in proliferating embryonic cerebral cortical precursors, and reciprocally, Fas-ligand modifies estrogen control of cell-cycle proteins
| Autor: | Newman Joseph M, Wade Stephen B, Santillano Daniel R, Cheema Zulfiqar F, Miranda Rajesh C |
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| Rok vydání: | 2003 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Fas Ligand Protein Blotting Western CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Cell Cycle Proteins lcsh:RC321-571 Cell-Matrix Junctions Rats Sprague-Dawley Cyclins Proliferating Cell Nuclear Antigen Animals fas Receptor lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Cells Cultured Cell Nucleus Cerebral Cortex Neurons Membrane Glycoproteins Stem Cells lcsh:QP351-495 Cell Cycle Intracellular Signaling Peptides and Proteins Estrogens Anoikis Flow Cytometry Extracellular Matrix Rats lcsh:Neurophysiology and neuropsychology Tumor Suppressor Protein p53 Carrier Proteins Research Article |
| Zdroj: | BMC Neuroscience BMC Neuroscience, Vol 5, Iss 1, p 11 (2004) |
| ISSN: | 1471-2202 |
| Popis: | Background Apoptosis is important for normal cerebral cortical development. We previously showed that the Fas suicide receptor was expressed within the developing cerebral cortex, and that in vitro Fas activation resulted in caspase-dependent death. Alterations in cell-surface Fas expression may significantly influence cortical development. Therefore, in the following studies, we sought to identify developmentally relevant cell biological processes that regulate cell-surface Fas expression and reciprocal consequences of Fas receptor activation. Results Flow-cytometric analyses identified two distinct neural sub-populations that expressed Fas on their cell surface at high (FasHi) or moderate (FasMod) levels. The anti-apoptotic protein FLIP further delineated a subset of Fas-expressing cells with potential apoptosis-resistance. FasMod precursors were mainly in G0, while FasHi precursors were largely apoptotic. However, birth-date analysis indicated that neuroblasts express the highest levels of cell-surface Fas at the end of S-phase, or after their final round of mitosis, suggesting that Fas expression is induced at cell cycle checkpoints or during interkinetic nuclear movements. FasHi expression was associated with loss of cell-matrix adhesion and anoikis. Activation of the transcription factor p53 was associated with induction of Fas expression, while the gonadal hormone estrogen antagonistically suppressed cell-surface Fas expression. Estrogen also induced entry into S-phase and decreased the number of Fas-expressing neuroblasts that were apoptotic. Concurrent exposure to estrogen and to soluble Fas-ligand (sFasL) suppressed p21/waf-1 and PCNA. In contrast, estrogen and sFasL, individually and together, induced cyclin-A expression, suggesting activation of compensatory survival mechanisms. Conclusions Embryonic cortical neuronal precursors are intrinsically heterogeneous with respect to Fas suicide-sensitivity. Competing intrinsic (p53, cell cycle, FLIP expression), proximal (extra-cellular matrix) and extrinsic factors (gonadal hormones) collectively regulate Fas suicide-sensitivity either during neurogenesis, or possibly during neuronal migration, and may ultimately determine which neuroblasts successfully contribute neurons to the differentiating cortical plate. |
| Databáze: | OpenAIRE |
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