Transforming growth factor-beta induced cell death in the developing chick retina is mediated via activation of c-jun N-terminal kinase and downregulation of the anti-apoptotic protein Bcl-X(L).
Cell death in general and especially in neuronal cells is regulated by a complex interplay between survival and death signals, generated by extracellular factors like neurotrophins and intracellular regulation mechanisms. The pleiotrophic transforming growth factor beta (TGF-beta) influences life and death decisions in cells depending on cell type and other growth factors present. It has been previously shown that TGF-beta is necessary to induce ontogenetic cell death during retinal development. In the present study, we analyzed the underlying intracellular signaling processes involved in TGF-beta mediated cell death. We established a cell culture system mimicking the situation of ontogenetic cell death in vivo with cultured retinal cells isolated from the retinae of embryonic day 7 white leghorn chick embryos. The neutralization of TGF-beta inhibits cell death of cultured retinal cells whereas exogenous application of TGF-beta is followed by enhanced apoptosis as observed by in situ cell death detection (terminal deoxynucleotidyl transferase-mediated nick end labeling) assay. TGF-beta induces the activation of c-jun N-terminal kinase in the mitogen-activated protein kinase (MAP kinase) pathway and provokes downregulation of the anti-apoptotic BCL-X(L) protein. Thus, TGF-beta influences cell death via activation of a pro-apoptotic MAP-kinase cascade accompanied by a downregulation of anti-apoptotic signals.
Schuster
Norbert
N
Department of Anatomy and Cell Biology, Medical Faculty, University of Saarland, D-66421 Homburg/Saar, Germany.
Dünker
Nicole
N
Krieglstein
Kerstin
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D012160:Retina / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051020:bcl-X Protein
D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases