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RESEARCH ARTICLE |
1 Department of Radiation Oncology, University of Tübingen, Hoppe-Seyler Str. 3, D-72076 Tübingen, Germany
2 Department of Physiology I, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany
3 Department of Immunology and Cell Biology, Institute of Experimental Dermatology, University of Münster, Röntgenstr. 21, D-48149 Münster, Germany
4 Department of Internal Medicine I, University of Tübingen, Ottfried-Müller Str. 10, D-72076 Tübingen, Germany
*Author for correspondence (e-mail: claus.belka{at}uni-tuebingen.de)
Accepted August 16, 2001
The proto-oncogene Bcl-2 is expressed in membranes of mitochondria and endoplasmic reticulum and mediates resistance against a broad range of apoptotic stimuli. Although several mechanisms of Bcl-2 action have been proposed, its role in different cellular organelles remains elusive. Here, we analyzed the function of Bcl-2 targeted specifically to certain subcellular compartments in Jurkat cells. Bcl-2 expression was restricted to the outer mitochondrial membrane by replacing its membrane anchor with the mitochondrial insertion sequence of ActA (Bcl-2/MT) or the ER-specific sequence of cytochrome b5 (Bcl-2/ER). Additionally, cells expressing wild-type Bcl-2 (Bcl-2/WT) or a transmembrane domain-lacking mutant (Bcl-2/
TM) were employed. Apoptosis induced by ionizing radiation or by the death receptors for CD95L or TRAIL was analyzed by determination of the mitochondrial membrane potential (
m) and activation of different caspases.
Bcl-2/WT and Bcl-2/MT strongly inhibited radiation-induced apoptosis and caspase activation, whereas Bcl-2/TM had completely lost its anti-apoptotic effect. Interestingly, Bcl-2/ER conferred protection against radiation-induced mitochondrial damage and apoptosis similarly to Bcl-2/MT. The finding that ER-targeted Bcl-2 interfered with mitochondrial m breakdown and caspase-9 activation indicates the presence of a crosstalk between both organelles in radiation-induced apoptosis. By contrast, Bcl-2 in either subcellular position did not influence CD95- or TRAIL-mediated apoptosis.
Key words: Bcl-2, Mitochondria, Endoplasmic reticulum, Apoptosis, Radiation, CD95
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