Related Experiment Video

Updated: Aug 8, 2026

A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
09:04

A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors

Published on: March 15, 2016

TSC2 regulates VEGF through mTOR-dependent and -independent pathways

James B Brugarolas1, Francisca Vazquez, Archana Reddy

  • 1Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.

Cancer Cell
|September 6, 2003
PubMed

Insights

Loss of the TSC2 tumor suppressor protein increases vascular tumors by regulating VEGF. This occurs through both mTOR-dependent and -independent pathways, potentially involving chromatin remodeling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Tuberous sclerosis complex (TSC) is caused by TSC2 inactivation, leading to vascular tumors.
  • TSC2 protein inhibits mTOR (mammalian target of Rapamycin), a key cellular regulator.
  • VEGF (Vascular Endothelial Growth Factor) is crucial for tumor vascularization.

Purpose of the Study:

  • To investigate the regulatory mechanisms of VEGF by TSC2.
  • To elucidate the roles of mTOR-dependent and -independent pathways in TSC2-mediated VEGF regulation.
  • To explore potential therapeutic targets for TSC-associated tumors.

Main Methods:

  • Cellular assays using TSC2-deficient cells and disease-associated mutants.
  • Western blotting to assess protein levels (HIF-1alpha, VEGF).
  • Treatment with Rapamycin (mTOR inhibitor) and Trichostatin A (HDAC inhibitor).

Main Results:

  • TSC2 loss leads to HIF-1alpha accumulation and increased VEGF expression.
  • Rapamycin normalizes HIF-1alpha levels in TSC2-deficient cells, confirming mTOR-dependent regulation.
  • Rapamycin only partially reduces VEGF, indicating an mTOR-independent pathway.
  • Trichostatin A downregulates VEGF in TSC2-deficient cells, suggesting chromatin remodeling involvement.

Conclusions:

  • TSC2 regulates VEGF through both mTOR-dependent and -independent pathways.
  • The mTOR-independent pathway may involve epigenetic modifications like chromatin remodeling.
  • Understanding these pathways offers insights into TSC pathogenesis and potential therapeutic strategies.

More Related Videos

Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis11:44

Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis

Published on: March 30, 2019

Three-dimensional Angiogenesis Assay System using Co-culture Spheroids Formed by Endothelial Colony Forming Cells and Mesenchymal Stem Cells09:24

Three-dimensional Angiogenesis Assay System using Co-culture Spheroids Formed by Endothelial Colony Forming Cells and Mesenchymal Stem Cells

Published on: September 18, 2019

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...