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The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination

Oncogene volume 19, pages 6306–6316 (2000)Cite this article

Abstract

We report here that overexpression of the tuberous sclerosis-1 (TSC1) gene product hamartin results in the inhibition of growth, as well as changes in cell morphology. Growth inhibition was associated with an increase in the endogenous level of the product of the tuberous sclerosis-2 (TSC2) gene, tuberin. As overexpression of tuberin inhibits cell growth, and hamartin is known to bind tuberin, these results suggested that hamartin stabilizes tuberin and this contributes to the inhibition of cell growth. Indeed, transient transfection of TSC1 increased the endogenous level of tuberin, and transient co-transfection of TSC1 with TSC2 resulted in higher tuberin levels. The stabilization was explained by the finding that tuberin is highly ubiquitinated in cells, while the fraction of tuberin that is bound to hamartin is not ubiquitinated. Co-expression of tuberin stabilized hamartin, which is weakly ubiquitinated, in transiently transfected cells. The amino-terminal two-thirds of tuberin was responsible for its ubiquitination and for stabilization of hamartin. A mutant of tuberin from a patient missense mutation of TSC2 was also highly ubiquitinated, and was unable to stabilize hamartin. We conclude that hamartin is a growth inhibitory protein whose biological effect is likely dependent on its interaction with tuberin.

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Acknowledgements

We thank Doug Lowy for comments and suggestions; Shauna Everett for expert assistance with photography; Silvio Gutkind for the HA-Ub plasmid; and Juan I. Bonifacino for technical assistance.

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Author notes

  1. Giovanna Benvenuto

    Present address: Department of Cellular and Molecular Biology and Pathology, Faculty of Medicine, University of Naples, Naples, Italy

  2. Giovanna Benvenuto and Shaowei Li: G Benvenuto and S LI contributed equally to this paper.

Authors and Affiliations

  1. Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD 20892, Maryland, USA

    Giovanna Benvenuto, Shaowei Li, Samantha J Brown, Richard Braverman, William C Vass & Jeffrey E DeClue

  2. Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, CF4 4XN, UK

    Jeremy P Cheadle & Julian R Sampson

  3. Department of Clinical Genetics, Erasmus University, Rotterdam, 3015 GE, The Netherlands

    Dicky JJ Halley

  4. Department of Dermatology, Klinikum Innenstadt, Ludwig-Maximilians-University, Munich, D-80337, Germany

    Ralf Wienecke

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Benvenuto, G., Li, S., Brown, S. et al. The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 19, 6306–6316 (2000). https://doi.org/10.1038/sj.onc.1204009

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