Tuberous Sclerosis Complex and the Mammalian Target of Rapamycin Pathways

Jane Yu, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

Published online: September 2010

DOI: 10.1002/9780470015902.a0022388

Tuberous sclerosis complex (TSC) is an autosomal dominant disease in which the mammalian target of rapamycin complex 1 (mTORC1) is hyperactivated. Lymphangioleiomyomatosis (LAM) is the pulmonary manifestation of TSC which occurs primarily in women. The TSC proteins tuberin and hamartin regulate the small guanosine triphophatase (GTPase) Rheb (Ras homologue enriched in brain), a direct activator of mTORC1. Activation of mTORC1 has been observed in TSC tumours and other human tumours, and mTORC1 inhibitors have been tested for the treatment of TSC and for malignancies including renal cancer. In this article, we discuss diagnostic features, updated molecular basis, evidences of mTORC1 activation, preclinical models and completed clinical trials of mTORC1 inhibitors in TSC. We also review the evidence of mTORC1-independent functions of the TSC proteins, and discuss future therapeutic perspectives combining mTORC1 inhibitors with agents targeting other cellular pathways.

Key Concepts:

  • Tuberous sclerosis complex (TSC) is a hereditary disease characterised by the development of seizures, mental retardation, autism and hamartomas in multiple organs including the brain, retina, kidney, heart and skin.
  • Lymphangioleiomyomatosis (LAM) is the metastatic pulmonary manifestation of TSC occurring almost exclusively in women, in whom the lungs are infiltrated with abnormal smooth muscle-like cells and there is degeneration of lung parenchyma.
  • Metastasis is the multistep process in which tumour cells at the primary site spread to distant tissues/organs to proliferate.
  • Loss of heterozygosity refers to the loss of a normal allele on a chromosome while the other allele has a genetic alteration or mutation.
  • Mammalian target of rapamycin (mTOR) refers to the FRAP1 gene product, a serine/threonine protein kinase that controls ribosome biogenesis, protein translation, cell growth and metabolism.

Keywords: tuberous sclerosis complex; lymphangioleiomyomatosis; Rheb; MTORC1; rapamycin; angiomyolipomas; metastasis; tumour suppressor; differentiation; signal transduction

Figure 1. Evidences support that LAM is a metastatic disease. (a) Same somatic mutation in TSC2 was found in angiomyolipomas and LAM lung, but not in normal kidney or peripheral blood (Carsillo et al., 2000). (b) Oestrogen promotes the lung colonisation of Tsc2-null ELT3 cells. Female ovariectomised CB17–severe combined immunodeficient (SCID) mice were implanted with estradiol (E2) (n=3) or placebo (n=3) pellets 1 week before cell injection. 2×105 ELT3-luciferase cells were injected intravenously. Lung colonisation was measured using bioluminescence at 1, 3 and 24 h after injection. Representative images are shown (Yu et al., 2009). Reproduced with permission from Proceedings of the National Academy of Sciences of the USA.
Figure 2. Tuberin and hamartin mediate signalling transduction to regulate cellular events. Tumour suppressor proteins tuberin (TSC2) and hamartin (TSC1) form a complex to suppress ciliary development and to inhibit the active form of the small GTPase Rheb (Rheb-GTP). GTP-bound Rheb activates mTOR complex 1 (mTORC1) which consists of mTOR, mLST8, Raptor, PRAS40 and Deptor; promotes ribosome biogenesis, protein translation, cell growth, metabolism and notch activation; and inhibits autophagy. Rheb also activates cell fate decision via notch, Hes-1 and Hey-1, and inhibits B-Raf and C-Raf activities. Hamartin is inactivated via phosphorylation by CDK1 and IKK. Tuberin is activated via phosphorylation by AMPK, and inactivated via phosphorylation by Akt, DAPK, ERK2, GSK3, MK2 and RSK1.
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Molecular Genetics of Common and Complex Disease | Genetics of Intelligence and Cognition | Specific Genetic Disorders | Linkage Analysis | Posttranslational Modification | Mechanisms of Cell Death, Senescence and Metabolism | Biomolecular Interactions | Cell Signalling | Proteins: Structure, Function, Metabolism | Enzymes: Structure and Action Mechanism
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Article Title: Tuberous Sclerosis Complex and the Mammalian Target of Rapamycin Pathways
 
How to Cite close
Yu, Jane(Sep 2010) Tuberous Sclerosis Complex and the Mammalian Target of Rapamycin Pathways. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022388]