Tumor Suppressor Protein Complex and Normal State
- Tumor suppressor protein complex formed by TSC1 and TSC2 binding: TSC may arise from a mutation in one of two genes, TSC1 (hamartin), with loci on 9q, or TSC2 (tuberin), with loci on 16p, which code for tumor suppressor protein complex.
- Complex inactivates Rheb: This tumor suppressor complex drives the GTPase, the Ras homolog enriched in brain protein, into the inactive state (guanosine diphosphate-bound state) via tuberin’s GTPase activating function.
- Decrease in mTOR stimulation lessens cell proliferation: The GTPase Ras homolog is enriched by a brain protein called Rheb, which in the (guanosine-triphosphate) active state acts to increase the mammalian target rapamycin (mTOR), a protein kinase that appears to be evolutionarily conserved. mTOR is a factor that serves to increase cell growth as opposed to cell proliferation (11).
mTOR Pathway Disinhibition and TSC
- Mutation of TSC1 or TSC2 inhibits tumor suppressor protein complex formation: In summary, if the tumor suppressor complex is fully functional, Rheb is driven into its inactive, guanosine diphosphate-bound state, lowering the mTOR signaling pathway’s effects.
- Rheb activity no longer influenced by tumor suppressor protein complex: Mutations, such as those causing TSC, result in the active, guanosine triphosphate Rheb. This active Rheb causes mTOR pathway signaling.
- Rheb stimulates mTOR activity and cell proliferation: mTOR acts through the protein Raptor,to increase cell growth and protein synthesis by phosphorylating protein s6 kinases (S6Ks) and effecting the eukaryotic initiation factor 4E binding protein 1 (4E-BP1) (11).
- Summary of TSC1 and TSC2 function: Functional tumor suppressors hamartin and tuberin cause a down-regulation of the mTOR pathway S6K1 and 4E-BP1, while mutations increase, thus producing TSC. The mutations lead to benign tumors in multiple organs, including the brain and heart (20).
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