Pathogenesis Of

Tuberous sclerosis hamartomas, particularly renal AMLs, usually display loss of heterozygosity (LOH) for the wildtype allele of either TSC1 or TSC2, consistent with a two-hit mechanism for complete inactivation of either TSC1 or TSC2.[3] This has not been seen as consistently for other types of TSC lesions, but microdissection has been effective in some cases (e.g., LAM) to demonstrate LOH events. Cortical tubers do not show evidence of LOH either, and cell admixture likely explains this finding.

Consistent with a relative lack of malignancy in TSC patients, limited surveys of human cancer specimens have failed to show evidence of either TSC1 or TSC2 mutation, with the possible exception of bladder carcinoma.

Seminal studies in Drosophila led to major insights into the cellular functions of TSC1 and TSC2.[8] Translation and extension of these studies in mammalian cells have led to a model of P13 K-Akt-TSC1/TSC2-Rheb-mTOR signaling that is shown in Fig. 2. In normal quiescent cells, P13 K and Akt are inactive, the TSC1/TSC2 complex is active as a GTPase activating protein (GAP) for Rheb, there are low levels of Rheb-GTP, and mTOR is inactive. In response to growth factor stimulation, P13 K and Akt become activated, TSC2 is phophorylated by Akt, and the TSC1/TSC2 complex becomes inactive as a GAP, so that Rheb-GTP levels rise, stimulating mTOR. In cells lacking TSC1 or TSC2, the residual TSC2 or TSC1 does not function as a GAP for Rheb, and Rheb-GTP levels are high, leading to constitutive activation of mTOR and phosphorylation of S6K1 and 4E-BP1. The model shown captures the main pathway involving TSC1 and TSC2, but omits many details and interconnections in the complex biochemical pathway that regulates cell growth. One

protein translation, cell growth

Fig. 2 Signaling pathway model for the function of TSC1 and TSC2 in mammalian cells. A phosphorylated growth factor receptor is shown at the upper left, to which a PI3 K molecule is binding. This leads to conversion of the indicated phosphoinositides to 3'-phosphoinositides, which leads to recruitment of Akt to the membrane in a position where it can be phosphorylated and activated by PDK1 and a second kinase. PTEN functions to terminate this signaling pathway by acting as a 3' phosphatase on these phosphoinositides. Activated pAkt phosphorylates TSC2 which inactivates its GAP activity. When active, TSC1/TSC2 complex serves as a GAP for Rheb, reducing levels of Rheb-GTP. Rheb-GTP activates mTOR by an uncertain mechanism (thus two arrows). ATP, phosphatidic acid (PA), and amino acids (AA) all influence mTOR activity, although the sensing mechanisms are unknown and likely indirect. Active mTOR phosphorylates 4E-BP1 and S6K1. p4E-BP1 releases from eIF4E, permitting formation of the eIF4F translation complex. pS6K1 phosphorylates S6, and together they activate the translational machinery. For simplicity only the main pathway involving TSC1, TSC2, and mTOR is shown. Arrows indicate positive actions and bars represent negative actions. TSC1 and TSC2 are used here and in the text to denote the corresponding proteins hamartin and tuberin.

protein translation, cell growth

Fig. 2 Signaling pathway model for the function of TSC1 and TSC2 in mammalian cells. A phosphorylated growth factor receptor is shown at the upper left, to which a PI3 K molecule is binding. This leads to conversion of the indicated phosphoinositides to 3'-phosphoinositides, which leads to recruitment of Akt to the membrane in a position where it can be phosphorylated and activated by PDK1 and a second kinase. PTEN functions to terminate this signaling pathway by acting as a 3' phosphatase on these phosphoinositides. Activated pAkt phosphorylates TSC2 which inactivates its GAP activity. When active, TSC1/TSC2 complex serves as a GAP for Rheb, reducing levels of Rheb-GTP. Rheb-GTP activates mTOR by an uncertain mechanism (thus two arrows). ATP, phosphatidic acid (PA), and amino acids (AA) all influence mTOR activity, although the sensing mechanisms are unknown and likely indirect. Active mTOR phosphorylates 4E-BP1 and S6K1. p4E-BP1 releases from eIF4E, permitting formation of the eIF4F translation complex. pS6K1 phosphorylates S6, and together they activate the translational machinery. For simplicity only the main pathway involving TSC1, TSC2, and mTOR is shown. Arrows indicate positive actions and bars represent negative actions. TSC1 and TSC2 are used here and in the text to denote the corresponding proteins hamartin and tuberin.

clinical correlate of this model is that hamartomas that occur in TSC both in patients and animal models typically express phospho-S6 and phospho-S6K1, signposts of activation of mTOR. Two consequences of activation of this pathway are the secretion of VEGF by cells in many TSC lesions and abnormal STAT phosphorylation.

The molecular basis of epileptogenesis induced by cortical tubers is uncertain, although disorganization of the cortex in these lesions likely contributes. There is increased transcription of genes encoding glutamatergic receptors by dysplastic neurons and giant cells in tubers, with reduced expression of gamma-aminobutyric acid (GABA)-ergic receptors.[7] These expression changes may contribute to epileptogenesis in TSC. Tuber giant cells and SEN cells also express pS6 and pS6K1, like other TSC lesions, consistent with complete inactivation of TSC1 or TSC2 with activation of mTOR as in other TSC hamartomas.

The TSC1/TSC2 complex has size 330 kDa, and the GAP domain of TSC2 comprises about 10 kDa of this complex. This alone suggests that there are other functions of the complex. TSC1 has been reported to bind to ezrin and other ERM family proteins, and appears to be involved in adhesion events and rho signaling to the actin cytoskeleton.[9] TSC2 has been reported to have a role in the membrane localization of polycystin-1 in renal epithelial cells.[10] A role for the TSC1/TSC2 complex in beta-catenin signaling has also been described. Whether any of these observations are independent of or relate to the role of TSC1/TSC2 in the P13 K signaling pathway is unknown.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

Get My Free Ebook


Post a comment