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Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2^sup -/-^ murine embryo fibroblast cultures display early senescence with overexpression of p21^sup CIP1/WAF1^ that is rescued by loss of TP53. Tsc2^sup -/-^TP53^sup -/-^ cells, as well as tumors from Tsc2^sup +/-^ mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2^sup -/-^TP53^sup -/-^ cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2^sup -/-^TP53^sup -/-^ and Tsc1^sup -/-^ cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFR[alpha] and PDGFR[beta] expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFR[beta] in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.
NonStandard abbreviations used: tuberous sclerosis (TSC); niurine embryo fibroblast (MEF); passage eight (P8); Earle's balanced salt solution (EBSS); Nonidet P-40 (NP-40); PH domain of Akt fused to YFP (YPH-Akt); yellow fluorescent protein (YFP); phospharidic acid (PA).
Introduction
Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome due to inactivating mutations in either of two genes, TSC1 and TSC2 (1-3). The tumors that occur in TSC are distinctive in that they typically consist of multiple cell types and replicate normal structures, and they are termed hamartomas. Cancer development is rare in TSC, occurring only in the kidney to an appreciable extent, where it is seen in 2-3% of all patients (2).
Null alleles of both Tsc1 and Tsc2 have been generated in the mouse (4-7). Heterozygotes for either gene develop multiple renal cystadenomas that progress at low frequency to renal carcinoma. Liver hemangioma are also seen in about half of heterozygous mice, are the most common cause of death in mice less...