TGF-beta superfamily members, ActivinA and TGF-beta1, induce apoptosis in oligodendrocytes by different pathways.
Activins and transforming growth factor (TGF)-betas, members of the TGF-beta superfamily, affect numerous physiological processes, including apoptosis, in a variety of organs and tissues. Apoptotic functions of TGF-betas, in contrast to those of the activins, are well documented in the developing and adult nervous system. TGF-betas operate in a context-dependent manner and cooperate with other cytokines in the regulation of apoptosis. In this study, we show, for the first time, an apoptotic function of ActivinA in the nervous system, i.e. in oligodendroglial progenitor cells. Using the oligodendroglial cell line OLI-neu, we show that ActivinA acts autonomously, without cooperating with TGF-beta. In contrast to the mechanism of TGF-beta-mediated apoptosis involving Bcl-xl down-regulation, Bcl-xl in ActivinA-induced apoptosis is classically sequestered by the BH3-only protein Puma. Puma expression is controlled by the transcription factor p53 as demonstrated by experiments with the p53 inhibitor Pifithrin-alpha. Furthermore, in the apoptotic TGF-beta pathway, caspase-3 is activated, whereas in the apoptotic ActivinA pathway, apoptosis-inducing factor is released to trigger DNA fragmentation. These data suggest that TGF-beta and ActivinA induce apoptosis in oligodendrocytes by different apoptotic pathways.
Schulz
Ramona
R
Centre of Anatomy, Department of Neuroanatomy, Georg August University, Goettingen, Germany.
Vogel
Tanja
T
Dressel
Ralf
R
Krieglstein
Kerstin
K
D028341:Activins / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D021381:Protein Transport / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; C422405:activin A; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D028341:Activins; D020169:Caspases