QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rudner, J. Articles by Belka, C. Search for Related Content PubMed PubMed Citation Articles by Rudner, J. Articles by Belka, C.

Wild-type, mitochondrial and ER-restricted Bcl-2 inhibit DNA damage-induced apoptosis but do not affect death receptor-induced apoptosis

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

This article has been cited by other articles:

				Y. Tambe, A. Yoshioka-Yamashita, K.-i. Mukaisho, S. Haraguchi, T. Chano, T. Isono, T. Kawai, Y. Suzuki, R. Kushima, T. Hattori, et al. Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs Carcinogenesis, April 1, 2007; 28(4): 777 - 784. [Abstract] [Full Text] [PDF]

				Y. Murakami, E. Aizu-Yokota, Y. Sonoda, S. Ohta, and T. Kasahara Suppression of Endoplasmic Reticulum Stress-induced Caspase Activation and Cell Death by the Overexpression of Bcl-xL or Bcl-2 J. Biochem., March 1, 2007; 141(3): 401 - 410. [Abstract] [Full Text] [PDF]

				P. Kumar, I. K. Coltas, B. Kumar, D. B. Chepeha, C. R. Bradford, and P. J. Polverini Bcl-2 Protects Endothelial Cells against {gamma}-Radiation via a Raf-MEK-ERK-Survivin Signaling Pathway That Is Independent of Cytochrome c Release Cancer Res., February 1, 2007; 67(3): 1193 - 1202. [Abstract] [Full Text] [PDF]

				F. A. Sinicrope, R. C. Penington, and X. M. Tang Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis Is Inhibited by Bcl-2 but Restored by the Small Molecule Bcl-2 Inhibitor, HA 14-1, in Human Colon Cancer Cells Clin. Cancer Res., December 15, 2004; 10(24): 8284 - 8292. [Abstract] [Full Text] [PDF]

				N. Morishima, K. Nakanishi, K. Tsuchiya, T. Shibata, and E. Seiwa Translocation of Bim to the Endoplasmic Reticulum (ER) Mediates ER Stress Signaling for Activation of Caspase-12 during ER Stress-induced Apoptosis J. Biol. Chem., November 26, 2004; 279(48): 50375 - 50381. [Abstract] [Full Text] [PDF]

				J. An, Y. Chen, and Z. Huang Critical Upstream Signals of Cytochrome c Release Induced by a Novel Bcl-2 Inhibitor J. Biol. Chem., April 30, 2004; 279(18): 19133 - 19140. [Abstract] [Full Text] [PDF]

				M. J. Thomenius and C. W. Distelhorst Bcl-2 on the endoplasmic reticulum: protecting the mitochondria from a distance J. Cell Sci., November 15, 2003; 116(22): 4493 - 4499. [Abstract] [Full Text] [PDF]

				J. M. Adams Ways of dying: multiple pathways to apoptosis Genes & Dev., October 15, 2003; 17(20): 2481 - 2495. [Full Text] [PDF]

				V. Jendrossek, S. Fillon, C. Belka, I. Muller, B. Puttkammer, and F. Lang Apoptotic Response of Chang Cells to Infection with Pseudomonas aeruginosa Strains PAK and PAO-I: Molecular Ordering of the Apoptosis Signaling Cascade and Role of Type IV Pili Infect. Immun., May 1, 2003; 71(5): 2665 - 2673. [Abstract] [Full Text] [PDF]

				M. Germain, J. P. Mathai, and G. C. Shore BH-3-only BIK Functions at the Endoplasmic Reticulum to Stimulate Cytochrome c Release from Mitochondria J. Biol. Chem., May 10, 2002; 277(20): 18053 - 18060. [Abstract] [Full Text] [PDF]