Interferon-gamma-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic target.

Pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML) are proliferative lesions that occur in sporadic patients, and at much higher frequency in patients with tuberous sclerosis (TSC). The TSC1 and TSC2 genes play a critical role in their pathogenesis. Here we report a marked decrease in interferon (IFN)-gamma expression in both sporadic and TSC-associated AML and LAM.

Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: a tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis.

Pulmonary lymphangioleiomyomatosis and abdominal angiomyolipoma are related lesions for which there is no authentic animal model. Both of these proliferative lesions occur in sporadic patients, and at much higher frequency in patients with tuberous sclerosis, which is due to mutations in the TSC1 and TSC2 genes. Tsc1+/- and Tsc2+/- mice frequently develop liver hemangioma.

Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models.

Tuberous sclerosis complex (TSC) is a familial tumor disorder for which there is no effective medical therapy. Disease-causing mutations in the TSC1 or TSC2 gene lead to increased mammalian target of rapamycin (mTOR) kinase activity in the conserved mTOR signaling pathway, which regulates nutrient uptake, cell growth, and protein translation. The normal function of TSC1 and TSC2 gene products is to form a complex that reduces mTOR kinase activity.

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.

Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin.

Mutation in either TSC1 or TSC2 causes the autosomal dominant disorder tuberous sclerosis, in which widespread hamartomas are seen, some of which have a high level of vascularization. Tuberous sclerosis complex (TSC) gene products negatively regulate mammalian target of rapamycin (mTOR) activity. We found that vascular endothelial growth factor (VEGF) is secreted by Tsc1- or Tsc2-null fibroblasts at high levels compared with wild-type cells.

Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma.

Mutations that inactivate either TSC1 or TSC2 cause tuberous sclerosis. We have used immunoblotting and immunohistochemical analysis to see whether there is phosphorylation of p70 S6 kinase, and the ribosomal S6 protein in angiomyolipomas occurring in tuberous scierosis. Hamartin (encoded by TSC1) and S6K was expressed in all samples.

A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells.

Tuberous sclerosis (TSC) is a autosomal dominant genetic disorder caused by mutations in either TSC1 or TSC2, and characterized by benign hamartoma growth. We developed a murine model of Tsc1 disease by gene targeting. Tsc1 null embryos die at mid-gestation from a failure of liver development.