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Tuberin activates the proapoptotic molecule BAD

Oncogene volume 25, pages 6467–6479 (2006)Cite this article

Abstract

TSC1, encoding hamartin, and TSC2, encoding tuberin, are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis (TSC). TSC affects ∼1 in 6000 individuals and is characterized by the development of tumors, named hamartomas, in different organs. Hamartin and tuberin form a complex, of which tuberin is assumed to be the functional component. The TSC proteins have been implicated in the control of cell cycle and cell size. In addition to enhanced growth, reduced death rates can lead to tumor development. Therefore, defects in the apoptosis-inducing pathways contribute to neoplastic cell expansion. Here, we show that tuberin triggers apoptosis, accompanied by downregulation of p70S6K activity and of phosphorylation of BAD on residue Ser136, and by upregulation of the interaction of BAD/BCL-2 and BAD/BCL-XL. AKT phosphorylation negatively regulates tuberin's potential to trigger apoptosis. Experiments with BAD−/− cells demonstrate BAD to be a mediator of tuberin's effects on the regulation of apoptosis. Tuberin interferes with insulin-like growth factor-1-induced BAD Ser136 phosphorylation and cell survival. Our work proposes a model in which tuberin-mediated inhibition of p70S6K activates BAD to heterodimerize with BCL-2 and BCL-XL to promote apoptosis. A mutation of TSC2 – as it occurs in TSC patients – attenuates this proapoptotic potential, underscoring the relevance of our findings for human pathophysiology.

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Acknowledgements

We thank Drs AJ Beavis, J Blenis, C Borner, J Cheadle, J Sampson, D Halley, M Nellist, B Manning and R Yeung for reagents. This research has been supported by the Herzfelder'sche Familienstiftung, Vienna, Austria and the Red Bull Company, Salzburg, Austria.

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Authors and Affiliations

  1. Medical Genetics, Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria

    A Freilinger, M Rosner & M Hengstschläger

  2. Institute of Clinical Pathology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria

    G Krupitza

  3. Departments of Pathology and Medicine, Harvard Medical School, Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA, USA

    M Nishino & S J Korsmeyer

  4. Department of Pediatrics, Medical University of Vienna, Währinger Gürtel, Vienna, Austria

    G Lubec

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  1. A Freilinger
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  2. M Rosner
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Correspondence to M Hengstschläger.

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Freilinger, A., Rosner, M., Krupitza, G. et al. Tuberin activates the proapoptotic molecule BAD. Oncogene 25, 6467–6479 (2006). https://doi.org/10.1038/sj.onc.1209660

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