Tuberous sclerosis

Curatolo, Paolo; Bombardieri, Roberta; Jóźwiak, Sergiusz

doi:10.1016/s0140-6736(08)61279-9

Cited by 986 publications

(975 citation statements)

References 146 publications

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“…Because AKT signaling is largely diminished by this feedback inhibition, tumors lacking TSC2 are usually benign and rarely metastasize to other organs (1). Here, we show that cell migration is also impaired in TSC2-deficient cells, thus, providing an underlying molecular mechanism for lack of aggressiveness in mutant TSC2-related tumors.…”

Section: Discussionmentioning

confidence: 62%

“…Loss of function mutations in the TSC2 gene are responsible for the pathogenesis of tuberous sclerosis and other hamartoma syndromes (1). TSC2 functions as a tumor suppressor by negatively controlling the mTOR-signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The mutations are found in genes encoding two tumor suppressors, tuberous sclerosis complexes TSC1 and TSC2, also named harmatin and tuberin, respectively (1). TSC1 and TSC2 function as a complex and exert their tumor suppressor function by negatively regulating the mTOR pathway (2).…”

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confidence: 99%

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Tuberous Sclerosis Complex 2 (TSC2) Regulates Cell Migration and Polarity through Activation of CDC42 and RAC1

Larson

Liu

Stevens

et al. 2010

Journal of Biological Chemistry

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The phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays important roles in regulating cell motility. TSC2, a downstream target of AKT, is a central player in negatively controlling cell proliferation and protein translation through suppressing the activity of mTOR (mammalian target of rapamycin). However, the function of TSC2 in regulating cell migration remains unclear. Here, we show that TSC2 plays a critical role in the control of cell spreading, polarity, and migration. TSC2-deficient fibroblast cells were impaired in their ability to spread and alter actin cytoskeleton upon stimulation with insulin-like growth factor-1. Using scratch-induced polarization assay, we demonstrate that TSC2 (؊/؊) fibroblast cells polarized poorly toward the wound compared with wild-type cells. Similarly, knockdown of TSC2 expression in colon cancer cells resulted in a marked decrease in cell motility. Functionally, the activation of CDC42-and RAC1-GTPase was largely reduced in TSC2 knock-out fibroblast and TSC2 knockdown cancer cells. Furthermore, overexpression of an activating p110␣ mutant or short term rapamycin treatment rescued the cell polarization defect in TSC2 (؊/؊) fibroblast cells. Concurrently, the activation of CDC42 and RAC1 increased. The defect in cell migration and CDC42 and RAC1 activation was reversed by reintroducing TSC2 back into TSC2 (؊/؊) fibroblast cells. Taken together, we identified a novel role of TSC2 in controlling cell polarity and migration by regulating CDC42 and RAC1 activation.Tuberous sclerosis is an autosomal dominant disorder characterized by formation of hamartomas in multiple organs, including the brain, kidney, heart, lung, and skin. The mutations are found in genes encoding two tumor suppressors, tuberous sclerosis complexes TSC1 and TSC2, also named harmatin and tuberin, respectively (1). TSC1 and TSC2 function as a complex and exert their tumor suppressor function by negatively regulating the mTOR pathway (2). In the TSC1-TSC2 complex, TSC1 functions as a membrane-tethering anchor protein, whereas TSC2 serves as a GTPase activation protein to promote GTP hydrolysis and inactivation of RHEB, a small G-protein activator of mTOR. Loss of function mutations in either the TSC1 or TSC2 gene lead to abnormal up-regulation of mTOR signaling and are associated with the pathogenesis of the disease. Recent studies have shown that the activity of TSC2 can be regulated by multiple signaling inputs in cells (3). For example, TSC2 lies downstream of the PI3K/AKT 2 pathway, and phosphorylation by Akt deceases the GTPase activation protein activity of TSC2 and subsequently actives mTOR (4, 5). On the other hand, phosphorylation by the nutrient-sensing kinase, AMPK, enhances its ability to inactivate RHEB, therefore turning off mTOR-dependent cell growth signaling (6). In addition, TSC2 plays a critical role in controlling the negative feedback regulation of PI3K/Akt signaling (7, 8). Specifically, whereas loss of TSC2 function in tuberous sclerosis and other hamartoma syndromes leads to hyperactivat...

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Tuberous Sclerosis Complex 2 (TSC2) Regulates Cell Migration and Polarity through Activation of CDC42 and RAC1

Larson

Liu

Stevens

et al. 2010

Journal of Biological Chemistry

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“…Tuberous sclerosis complex (TSC) is a variably expressed autosomal dominant genetic disorder that is pathologically characterized by the presence of benign, non-invasive, tumor-like lesions (hamartomas) in multiple organ systems, including the brain, heart, skin, kidney, lung, and liver [1]. This relatively common single gene disorder affects both adults and children, with an estimated birth incidence of approximately 1 in 6000 [2, 3].…”

Section: Introductionmentioning

confidence: 99%

mTOR Inhibitors in Tuberous Sclerosis Complex

Curatolo

Moavero

2012

Current Neuropharmacology

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Tuberous sclerosis complex (TSC) is a genetic multiple organ system disorder that is characterized by the development of tumor-like lesions (hamartomas) and neurodevelopmental disorders. Mutations in the TSC1 and TSC2 tumor suppressor genes occur in the majority of patients with TSC, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for patients with TSC. Everolimus is the first mTOR inhibitor approved as a treatment option in the USA and in Europe for patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. The clinical evidence to date supports the use of mTOR inhibitors in a variety of TSC-associated disease manifestations, including SEGAs, renal angiomyolipoma, skin manifestations, and epilepsy. Furthermore, ongoing clinical trials evaluating mTOR inhibitors in TSC are underway, and the results of these studies are expected to provide further evidence that will firmly establish their role in this setting. This article will discuss the role of the mTOR pathway in TSC and review the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of mTOR inhibitors, along with their current place in clinical practice.

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“…There are two variants of this tumor; one is associated with tuberous sclerosis complex (TSC) and the other is sporadic. TSC is a multisystem, autosomal disease with various presentations, such as mental retardation, epilepsy, dermatological manifestation, renal AML and pulmonary lymphangiomyomatosis (1,2). Approximately 20% of renal AML cases are associated with TSC, in which 70-90% are bilateral (3,4).…”

Section: Introductionmentioning

confidence: 99%

Total nephrectomy with nephron-sparing surgery for a giant bilateral renal angiomyolipoma: A case report

Zhou

Tang

et al. 2015

Oncology Letters

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Abstract. The current report presents the case of a 50-year-old female who presented with a giant bilateral renal angiomyolipoma (AML). After assessing the patient's symptoms, the tumor size and renal function, the patient underwent a total nephrectomy for the right AML, which measured 28x20x14 cm and nephron-sparing surgery was performed without preoperative selective angiographic embolization for a further 3 AMLs in the left kidney, the largest of which had a diameter of 12 cm. The introperative bleeding volume was at an acceptable level and the renal function was stable. No local recurrence was observed and no dialysis was required during follow-up. The strategy of the treatment in this report should be considered when treating similar tumors.

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Tuberous sclerosis

Cited by 986 publications

References 146 publications

Tuberous Sclerosis Complex 2 (TSC2) Regulates Cell Migration and Polarity through Activation of CDC42 and RAC1

Tuberous Sclerosis Complex 2 (TSC2) Regulates Cell Migration and Polarity through Activation of CDC42 and RAC1

mTOR Inhibitors in Tuberous Sclerosis Complex

Total nephrectomy with nephron-sparing surgery for a giant bilateral renal angiomyolipoma: A case report

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