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A novel Bcl-x splice product, Bcl-xAK, triggers apoptosis in human melanoma cells without BH3 domain

Oncogene volume 25, pages 2160–2169 (2006)Cite this article

Abstract

Pro- and antiapoptotic proteins of the large Bcl-2 family are critical regulators of apoptosis via the mitochondrial pathway. Whereas antiapoptotic proteins of the family share all four Bcl-2 homology domains (BH1–BH4), proapoptotic members may lack some of these domains, but all so far described proapoptotic Bcl-2 proteins enclose BH3. The bcl-x gene gives rise to several alternative splice products resulting in proteins with distinct functions as the antiapoptotic Bcl-xL and proapoptotic Bcl-xS. Here, we describe a novel Bcl-x splice product of 138 amino acids termed Bcl-xAK (Atypical Killer), which encloses the Bcl-2 homology domains BH2 and BH4 as well as the transmembrane domain, but lacks BH1 and BH3. Weak endogenous expression of Bcl-xAK was seen in melanoma and other tumor cells. Interestingly, its overexpression by applying a tetracycline-inducible expression system resulted in significant induction of apoptosis in melanoma cells, which occurred in synergism with drug-induced apoptosis. After exogenous overexpression, Bcl-xAK was localized both in mitochondrial and in cytosolic cell fractions. By these findings, a completely new class of Bcl-2-related proteins is introduced, which promotes apoptosis independently from the BH3 domain and implies additional, new mechanisms for apoptosis regulation in melanoma cells.

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Abbreviations

NHM:

normal human melanocytes

RT–PCR:

reverse transcriptase–polymerase chain reaction

LDH:

lactate dehydrogenase

BH domain:

Bcl-2 homology domain

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Acknowledgements

The study was supported by grants from the Deutsche Krebshilfe/Mildred-Scheel-Stiftung (10-1434-Eb2), the Deutsche Forschungsgemeinschaft (SFB 366, TP B8) and the Sonnenfeld Stiftung, Berlin.

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Authors and Affiliations

  1. Department of Dermatology and Allergy, Skin cancer center, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, 12203, Germany

    A M Hossini, C C Geilen, L F Fecker & J Eberle

  2. Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Campus Berlin Buch, Berlin, 13125, Germany

    P T Daniel

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  1. A M Hossini
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  2. C C Geilen
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  3. L F Fecker
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  4. P T Daniel
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  5. J Eberle
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Correspondence to J Eberle.

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Hossini, A., Geilen, C., Fecker, L. et al. A novel Bcl-x splice product, Bcl-xAK, triggers apoptosis in human melanoma cells without BH3 domain. Oncogene 25, 2160–2169 (2006). https://doi.org/10.1038/sj.onc.1209253

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