Tuberous sclerosis and insulin resistance. Unlikely bedfellows reveal a TORrid affair.
The TSC1-TSC2 tumor suppressor complex serves as an interface between insulin and nutrient signaling pathways and the cell growth machinery. Recent work has indicated that the TSC1-TSC2 complex plays a role in the pathobiology of a number of tumor predisposition syndromes, including tuberous sclerosis (TSC1/2), Peutz-Jeghers syndrome (LKB1), and Cowden's syndrome (PTEN), in which the TSC/Rheb/mTOR axis is inappropriately active secondary to loss of tumor suppressor function. Recent work has demonstrated that TSC deficiency imposes a negative autoregulatory loop that suppresses insulin signaling at the post-receptor level, effectively resulting in cell autonomous insulin resistance. Exploitation of this insulin signaling deficiency may hold promise among tailored clinical therapies designed to manage tuberous sclerosis.
Shah
O Jameel
OJ
Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
Hunter
Tony
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010580:Peutz-Jeghers Syndrome / Q000235:genetics / Q000503:physiopathology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000503:physiopathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010750:Phosphoproteins; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins