Cited by 828PI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex ResearchMetabolism, Diabetes, and Cancer

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Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling

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Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the TSC1 or TSC2 genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). First, coexpression of hamartin and tuberin repressed phosphorylation of 4E-BP1, resulting in increased association of 4E-BP1 with eIF4E; importantly, a mutant of TSC2 derived from TSC patients was defective in repressing phosphorylation of 4E-BP1. Second, the activity of S6K1 was repressed by coexpression of hamartin and tuberin, but the activity of rapamycin-resistant mutants of S6K1 were not affected, implicating mTOR in the TSC-mediated inhibitory effect on S6K1. Third, hamartin and tuberin blocked the ability of amino acids to activate S6K1 within nutrient-deprived cells, a process that is dependent on mTOR. These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR and suggest that the formation of tumors within TSC patients may result from aberrantly high levels of mTOR-mediated signaling to downstream targets.

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Crossref · 10.1073/pnas.202476899

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Research works printed but not linked: 4

  1. E R Gomez, J R Sampson, V H Whittemore Developmental Perspectives in Psychiatry (Oxford Univ. Press, Oxford, 1999).
  2. T L Plank, R S Yeung, E P Henske Cancer Res 58, 4766–4770 (1998).
  3. Martin K. A. & Blenis J. (2002) Adv. Cancer Res. 86 in press.
  4. D Rousseau, A C Gingras, A Pause, N Sonenberg Oncogene 13, 2415–2420 (1996).

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Metadata

Authors
Tee, A. R., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C., & Blenis, J.
Affiliations
Brigham and Women's Hospital (US)
Corresponding author
Blenis, John
Venue
Proceedings of the National Academy of Sciences
Published
2002-09-23
Volume
99
Issue
21
Pages
13571-13576
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2087812126
Cited by
827
References
31
Citations by year
2026: 9 · 2025: 13 · 2024: 17 · 2023: 27 · 2022: 29 · 2021: 35 · 2020: 40 · 2019: 22 · 2018: 37 · 2017: 35 · 2016: 31 · 2015: 45 · 2014: 28 · 2013: 43 · 2012: 42
FWCI
17.27
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (GM 41890, GM51405, R01GM056203, GM 56203, R01GM051405, R01GM041890, R37GM041890)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
tuberous sclerosis complex, TSC1, TSC2, hamartin, tuberin, mTOR signaling, 4E-BP1, S6K1, amino acid signaling, nutrient deprivation, rapamycin resistance, protein phosphorylation, eIF4E, tumor formation
MeSH terms
Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Amino Acids, Carrier Proteins, Cell Line, Humans, Insulin, Models, Biological, Phosphoproteins, Phosphorylation, Protein Kinases, Proteins, Repressor Proteins, Tuberous Sclerosis, Signal Transduction, Point Mutation, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, TOR Serine-Threonine Kinases, In Vitro Techniques

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