Cited by 528Tuberous Sclerosis Complex ResearchPI3K/AKT/mTOR signaling in cancerCancer, Hypoxia, and Metabolism

TSC2 regulates VEGF through mTOR-dependent and -independent pathways

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Brugarolas, James B, Vazquez, Francisca, Reddy, Archana, Sellers, William R, Kaelin, William G·2003·Cancer Cell

Abstract

Inactivation of the TSC2 tumor suppressor protein causes tuberous sclerosis complex (TSC), a disease characterized by highly vascular tumors. TSC2 has multiple functions including inhibition of mTOR (mammalian target of Rapamycin). We found that TSC2 regulates VEGF through mTOR-dependent and -independent pathways. TSC2 loss results in the accumulation of HIF-1alpha and increased expression of HIF-responsive genes including VEGF. Wild-type TSC2, but not a disease-associated TSC2 mutant, downregulates HIF. Rapamycin normalizes HIF levels in TSC2(-/-) cells, indicating that TSC2 regulates HIF by inhibiting mTOR. In contrast, Rapamycin only partially downregulates VEGF in this setting, implying an mTOR-independent link between TSC2 loss and VEGF. This pathway may involve chromatin remodeling since the HDAC inhibitor Trichostatin A downregulates VEGF in TSC2(-/-) cells.

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Crossref · 10.1016/s1535-6108(03)00187-9

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  • Inactivating mutations in PTEN or TSC, as well as activating mutations in PI3K or AKT, lead to increased TORC1 activity that promotes HIF-α stabilization.

    “Inactivating mutations in phosphatase and tensin homolog (PTEN) or the tuberosis sclerosis complex (TSC) complex, as well as activating mutations in phosphatidylinositol 3-kinase (PI3K) or AKT, lead to increased TORC1 activity that promotes HIF-α stabilization”

    From Hypoxic control of metastasis (2016) · cites this paper as [30]

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Authors
Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R., & Kaelin, W. G.
Affiliations
Brigham and Women's Hospital (US)
Corresponding author
Kaelin, William G
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2003-08
Volume
4
Issue
2
Pages
147-158
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2062997257
Cited by
528
References
89
Citations by year
2026: 9 · 2025: 6 · 2024: 4 · 2023: 17 · 2022: 12 · 2021: 15 · 2020: 19 · 2019: 17 · 2018: 13 · 2017: 25 · 2016: 22 · 2015: 21 · 2014: 20 · 2013: 29 · 2012: 24
FWCI
17.63
Type
journal article
Language
en
Open access
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
TSC2, tuberous sclerosis complex, vascular endothelial growth factor, mTOR, HIF-1α, hypoxia, rapamycin, trichostatin A, chromatin remodeling, tumor vascularization, tumor suppressor inactivation
MeSH terms
Tuberous Sclerosis Complex 2 Protein, Animals, Hypoxia, Cells, Cultured, Gene Expression Regulation, Hydroxamic Acids, Phosphoglycerate Kinase, Phosphopyruvate Hydratase, Protein Kinases, Repressor Proteins, Transcription Factors, Transcription, Genetic, Gene Deletion, Ribosomal Protein S6 Kinases, Sirolimus, Tumor Suppressor Proteins, Excitatory Amino Acid Transporter 2, Vascular Endothelial Growth Factor A, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases

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