Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease
ABSTRACT The most exciting advances in the tuberous sclerosis complex (TSC) field occurred in 1993 and 1997 with the cloning of the TSC2 and TSC1 genes, respectively, and in 2003 with the identification of Rheb as the target of tuberin's (TSC2) GTPase activating protein (GAP) domain. Rheb has a dual role: it activates mTOR and inactivates B-Raf. Activation of mTOR leads to increased protein synthesis through phosphorylation of p70S6K and 4E-BP1. Upon insulin or growth factor stimulation, tuberin is phosphorylated by several kinases, including AKT/PKB, thereby suppressing its GAP activity and activating mTOR. Phosphorylation of hamartin (TSC1) by CDK1 also negatively regulates the activity of the hamartin/tuberin complex. Despite these biochemical advances, exactly how mutations in TSC1 or TSC2 lead to the clinical manifestations of TSC is far from being understood. Two of the most unusual phenotypes in TSC are the apparent metastasis of benign cells carrying TSC1 and TSC2 mutations, resulting in pulmonary lymphangiomyomatosis, and the ability of cells with TSC1 or TSC2 mutations to differentiate into the separate components of renal angiomyolipomas (vessels, smooth muscle and fat). We will discuss how the TSC signaling pathways are affected by mutations in TSC1 or TSC2, focusing on how these mutations may lead to the renal and pulmonary manifestations of TSC.
Full-textDOI: · Available from: Elizabeth Petri Henske, May 30, 2015
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ABSTRACT: AimsThe significance of the epithelioid type and the corresponding molecular alterations in hepatic angiomyolipoma (AML) have not been elucidated.Methods and resultsWe retrieved 24 samples of hepatic AML to delineate the clinicopathological features and the immunohistochemical expression of components in mTOR pathway, and employed microsatellite markers for analyzing allelic imbalances in the TSC1/TSC2 regions. Myomatous AML was the most common type and a predominantly epithelioid cell population was observed in 50% of the samples. Two thirds of all samples contained less than 20% of fat tissue. Four cases of monotypic epithelioid AML were discovered without prognostic implication. Elevated phospho-p70S6K expression was noted in 19 samples in the absence of phospho-AKT activity. Loss of heterogeneity (LOH) of TSC1/TSC2 gene was found in 15 samples. Compared to syndromic AML samples, sporadic AML sample exhibited LOH of microsatellite markers in a limited fashion. Only 4 samples had increased β-catenin expression in the context of concurrent high expression of phospho-p70S6K and phospho-S6 (p = 0.018).Conclusions The a low fat content and epithelioid cytomorphology in hepatic AML potentially obstruct preoperative and pathological diagnosis. Alteration of the mTOR pathway and LOH of the TSC genes is a frequent pathogenesis in hepatic AMLs.This article is protected by copyright. All rights reserved.Histopathology 09/2014; 66(5). DOI:10.1111/his.12551 · 3.30 Impact Factor
Frontiers in Bioscience 01/2011; 16(1):1461. DOI:10.2741/3799 · 4.25 Impact Factor
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ABSTRACT: PI3K/AKT signaling leads to reduced apoptosis, stimulates growth and increases proliferation. Under normal conditions, activation is tightly controlled and dependent on both extracellular growth signals and the availability of amino acids and glucose. Genetic aberrations leading to PI3K/AKT hyper-activation are observed at considerable frequency in all major nodes in most tumors. In colorectal cancer the most commonly observed pathway changes are IGF2 overexpression, PIK3CA mutations and PTEN mutations and deletions. Combined, these alterations are found in about 40% of large bowel tumors. In addition, but not mutually exclusive to these, KRAS mutations are observed at a similar frequency. There are however additional, less frequent and more poorly understood events that may also push the PI3K/AKT pathway into overdrive and thus promote malignant growth. Here we discuss aberrations of components at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational level where perturbations may drive excessive PI3K/AKT signaling. Integrating multiple molecular levels will advance our understanding of this cancer critical circuit and more importantly, improve our ability to pharmacologically target the pathway in view of clonal development, tumor heterogeneity and drug resistance mechanisms. In this review, we revisit the PI3K/AKT-pathway cancer susceptibility syndromes, summarize the known aberrations at the different regulatory levels and the prognostic and predictive values of these alterations in colorectal cancer. Copyright © 2014. Published by Elsevier B.V.Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 11/2014; 1855(1). DOI:10.1016/j.bbcan.2014.09.008 · 7.58 Impact Factor