Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors.
Disruption of the TSC1 or TSC2 gene leads to the development of tumors in multiple organs, most commonly affecting the kidney, brain, lung, and heart. Recent genetic and biochemical studies have identified a role for the tuberous sclerosis gene products in phosphoinositide 3-kinase signaling. On growth factor stimulation, tuberin, the TSC2 protein, is phosphorylated by Akt, thereby releasing its inhibitory effects on p70S6K. Here we demonstrate that primary tumors from tuberous sclerosis complex (TSC) patients and the Eker rat model of TSC expressed elevated levels of phosphorylated mammalian target of rapamycin (mTOR) and its effectors: p70S6K, S6 ribosomal protein, 4E-BP1, and eIF4G. In the Eker rat, short-term inhibition of mTOR by rapamycin was associated with a significant tumor response, including induction of apoptosis and reduction in cell proliferation. Surprisingly, these changes were not accompanied by significant alteration in cyclin D1 and p27 levels. Our data provide in vivo evidence that the mTOR pathway is aberrantly activated in TSC renal pathology and that treatment with rapamycin appears effective in the preclinical setting.
Kenerson
Heidi L
HL
Department of Surgery, University of Washington, Seattle 98195, USA.
Aicher
Lauri D
LD
True
Lawrence D
LD
Yeung
Raymond S
RS
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D018095:Germ-Line Mutation; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus