Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by widespread development of hamartomas, which is caused by mutations in either TSC1 or TSC2. We demonstrate a dramatic decrease of IFN-gamma expression in tumors and mouse embryo fibroblast cell lines that lack either Tsc1 or Tsc2, which is reversed by rapamycin (mammalian target of rapamycin inhibitor) therapy. Increased signal transducers and activators of transcription (STAT) 1 expression and phosphorylation at Ser 727 and increased pSTAT3 Tyr705 levels also are seen in Tsc1 null and Tsc2 null cells and in tumors. Treatment of Tsc1 or Tsc2 null cells with IFN-gamma induces apoptosis, in contrast to control cell lines, with reduction in pSTAT3 Tyr705 levels and major increases in pSTAT1 Tyr701, bax, and caspase-1 and -9 levels. A combination of IFN-gamma and rapamycin is markedly synergistic in induction of apoptosis in Tsc1 or Tsc2 null cells because pSTAT3 Tyr705 phosphorylation is abolished completely and the other effects of IFN-gamma are maintained or enhanced. Rapamycin-IFN-gamma has unique potential therapeutic benefit for management of TSC tumors.
El-Hashemite
Nisreen
N
Brigham and Women's Hospital, Hematology Division, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zhang
Hongbing
H
Walker
Victoria
V
Hoffmeister
Karin M
KM
Kwiatkowski
David J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004357:Drug Synergism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D020123:Sirolimus / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D004268:DNA-Binding Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D020123:Sirolimus