What is the role of mammalian target of rapamycin (mTOR) in the pathogenesis of tuberous sclerosis complex (TSC)?

Updated: Aug 21, 2018
  • Author: David Neal Franz, MD; Chief Editor: Amy Kao, MD  more...
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mTOR, a major effector of cell growth (as opposed to cell proliferation) functions, among other things, as a sort of master switch for cellular anabolism versus catabolism, and it has important regulatory functions for cell volume and protein synthesis. It is also regulated by a wide variety of other factors, including insulin and amino acids. mTOR is a highly conserved protein kinase in evolution and is present in a wide range of organisms, from yeast, to Drosophila, to mammals.

Mutations in either hamartin or tuberin drive Rheb into the GTP-bound state, which results in constitutive mTOR signaling. mTOR appears to mediate many of its effects on cell growth through the phosphorylation of the ribosomal protein S6 kinases (S6Ks) and the repressors of protein synthesis initiation factor eIF4E, the 4EBPs. The S6Ks act to increase cell growth and protein synthesis, whereas the 4EBPs serve to inhibit these processes. mTOR interacts with the S6Ks and the 4EBPs through an associated protein, Raptor. When mTOR is constitutively activated through mutations in either hamartin or tuberin this results in the hamartomatous lesions of tuberous sclerosis in the brain, kidneys, heart, lungs, and other organs.

Rapamycin is capable of inducing regression of renal angiomyolipomas in animal models of TSC, and this effect appears to be enhanced by interferon-gamma, whose receptors are up-regulated by overactivity of mTOR. This pathway may be excessively active in other human malignancies as well as in TSC. These observations raise the possibility of new therapeutic interventions for this disorder. Trials of rapamycin for renal angiomyolipomas in humans with TSC have been completed (see Treatment section). Multicenter, randomized, placebo-controlled studies investigating RAD001 (everolimus) in the treatment of angiomyolipomatas (AMLs) and subependymal giant cell astrocytomas (SEGAs) are currently underway. On November 1, 2010, everolimus was approved by the US Food and Drug Administration (FDA) for SEGAs associated with tuberous sclerosis that cannot be treated with surgery.

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