Tuberous sclerosis genes regulate cellular 14-3-3 protein levels |
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| Authors: | Hengstschläger Markus Rosner Margit Fountoulakis Michael Lubec Gert |
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| Affiliation: | 1. Obstetrics and Gynecology, University of Vienna, Prenatal Diagnosis and Therapy, Währinger Gürtel 18-20, Vienna A-1090, Austria;2. F. Hoffman-La Roche, Ltd., CNS Preclinical Research, Grenzacherstrasse 124, Basel CH-4070, Switzerland;3. Department of Pediatrics, University of Vienna, Währinger Gürtel 18-20, Vienna A-1090, Austria;1. Brookhaven National Laboratory, Medical Department, Bldg 490, 30 Bell Ave Upton, NY 11793, USA;2. Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA;3. Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA;1. Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, School of Medicine, Ningbo University, Ningbo 315010, PR China;2. The Children’s Hospital of Zhejiang University, School of Medicine, Hangzhou 310003, PR China;1. A. N. Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky Prospect 33, Moscow 119071, Russian Federation;2. Department of Biochemistry, School of Biology, Moscow State University, Moscow 119991, Russian Federation;1. Departments of Surgery and Bioengineering, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA;2. University of Pittsburgh Medical Center, UPMC Mercy Hospital Trauma Services and Burn Unit, Pittsburgh, PA, USA |
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| Abstract: | The genes TSC1, encoding hamartin, and TSC2, encoding tuberin are responsible for tuberous sclerosis. This autosomal dominant tumor suppressor gene syndrome affects about 1 in 6000 individuals. A variety of tumors characteristically occur in different organs of tuberous sclerosis patients and are believed to result from defects in cell cycle/cell size control. We performed a proteomics approach of two-dimensional gel electrophoresis with subsequent mass spectrometrical identification of protein spots after ectopic overexpression of human TSC1 or TSC2. We found the cellular levels of four isoforms of the 14-3-3 protein family, 14-3-3 gamma, 14-3-3, 14-3-3 sigma, and 14-3-3 zeta, to be regulated by the two tuberous sclerosis gene products. In the same experiments the protein levels of keratin 7, capZ alpha-1 subunit, ezrin, and nedasin were not affected by ectopic TSC1 or TSC2. Western blot analyses confirmed the deregulation of 14-3-3 proteins upon ectopic overexpression of TSC1 and TSC2. A TSC1 mutant not encoding the transmembrane domain and the tuberin-binding domain but harbouring most of the coiled-coil region and the ERM protein interaction domain of hamartin did not affect 14-3-3 protein levels. The here presented findings suggest that deregulation of 14-3-3 protein amounts might contribute to the development of tumors in tuberous sclerosis patients. These data provide important new insights into the molecular development of this disease especially since both, the TSC genes and the 14-3-3 proteins, are known to be involved in mammalian cell cycle control. |
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