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Journal articles on the topic 'Tsc1, Tsc2'

Author: Grafiati

Published: 4 June 2021

Last updated: 16 February 2022

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1

Kwiatkowski, David. "Cancer Genetics: TSC1, TSC2, TSC3? or mosaicism?" European Journal of Human Genetics 13, no. 6 (2005): 695–96. http://dx.doi.org/10.1038/sj.ejhg.5201412.

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2

Goncharova, Elena, Dmitry Goncharov, Daniel Noonan, and Vera P. Krymskaya. "TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase." Journal of Cell Biology 167, no. 6 (2004): 1171–82. http://dx.doi.org/10.1083/jcb.200405130.

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Tuberous sclerosis complex (TSC) 1 and TSC2 are thought to be involved in protein translational regulation and cell growth, and loss of their function is a cause of TSC and lymphangioleiomyomatosis (LAM). However, TSC1 also activates Rho and regulates cell adhesion. We found that TSC2 modulates actin dynamics and cell adhesion and the TSC1-binding domain (TSC2-HBD) is essential for this function of TSC2. Expression of TSC2 or TSC2-HBD in TSC2−/− cells promoted Rac1 activation, inhibition of Rho, stress fiber disassembly, and focal adhesion remodeling. The down-regulation of TSC1 with TSC1 siRN

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3

Wang, Yanye, Song Xu, Shikang Zhao, et al. "Clinical and molecular characteristics of TSC1/2 mutant lung cancer." Journal of Clinical Oncology 38, no. 15_suppl (2020): e21647-e21647. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e21647.

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e21647 Background: Tumor suppressor genes TSC1 and TSC2 inhibit cell growth through inactivation the function of mTORC1. Previous studies have demonstrated that loss of function mutation of either TSC1 or TSC2 gene result in formation of neoplasm in multiple tissues. However, the clinical significance of TSC1 and TSC2 in non-small-cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the clinical and molecular characteristics of TSC1 and TSC2 mutation in NSCLC patients. Methods: We retrieved the clinical and genomic information of 1144 NSCLC from the Pan-Lung cancer dataset

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Hoogeveen-Westerveld, Marianne, Leontine van Unen, Ans van den Ouweland, Dicky Halley, Andre Hoogeveen, and Mark Nellist. "The TSC1-TSC2 complex consists of multiple TSC1 and TSC2 subunits." BMC Biochemistry 13, no. 1 (2012): 18. http://dx.doi.org/10.1186/1471-2091-13-18.

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5

Gan, Boyi, Zara K. Melkoumian, Xiaoyang Wu, Kun-Liang Guan, and Jun-Lin Guan. "Identification of FIP200 interaction with the TSC1–TSC2 complex and its role in regulation of cell size control." Journal of Cell Biology 170, no. 3 (2005): 379–89. http://dx.doi.org/10.1083/jcb.200411106.

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FIP200 (focal adhesion kinase [FAK] family interacting protein of 200 kD) is a newly identified protein that binds to the kinase domain of FAK and inhibits its kinase activity and associated cellular functions. Here, we identify an interaction between FIP200 and the TSC1–TSC2 complex through FIP200 binding to TSC1. We found that association of FIP200 with the TSC1–TSC2 complex correlated with its ability to increase cell size and up-regulate S6 kinase phosphorylation but was not involved in the regulation of cell cycle progression. Conversely, knockdown of endogenous FIP200 by RNA interference

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6

Huang, Jingxiang, and Brendan D. Manning. "A complex interplay between Akt, TSC2 and the two mTOR complexes." Biochemical Society Transactions 37, no. 1 (2009): 217–22. http://dx.doi.org/10.1042/bst0370217.

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Akt/PKB (protein kinase B) both regulates and is regulated by the TSC (tuberous sclerosis complex) 1–TSC2 complex. Downstream of PI3K (phosphoinositide 3-kinase), Akt phosphorylates TSC2 directly on multiple sites. Although the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1–TSC2 complex on Rheb and mTORC1 [mTOR (mammalian target of rapamycin) complex] 1, thereby activating mTORC1 in response to growth factors. Through negative-feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularl

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Huang, Jingxiang, Christian C. Dibble, Mika Matsuzaki, and Brendan D. Manning. "The TSC1-TSC2 Complex Is Required for Proper Activation of mTOR Complex 2." Molecular and Cellular Biology 28, no. 12 (2008): 4104–15. http://dx.doi.org/10.1128/mcb.00289-08.

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ABSTRACT The mammalian target of rapamycin (mTOR) is a protein kinase that forms two functionally distinct complexes important for nutrient and growth factor signaling. Both complexes phosphorylate a hydrophobic motif on downstream protein kinases, which contributes to the activation of these kinases. mTOR complex 1 (mTORC1) phosphorylates S6K1, while mTORC2 phosphorylates Akt. The TSC1-TSC2 complex is a critical negative regulator of mTORC1. However, how mTORC2 is regulated and whether the TSC1-TSC2 complex is involved are unknown. We find that mTORC2 isolated from a variety of cells lacking

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8

Bilanges, Benoit, Rhoda Argonza-Barrett, Marina Kolesnichenko, et al. "Tuberous Sclerosis Complex Proteins 1 and 2 Control Serum-Dependent Translation in a TOP-Dependent and -Independent Manner." Molecular and Cellular Biology 27, no. 16 (2007): 5746–64. http://dx.doi.org/10.1128/mcb.02136-06.

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ABSTRACT The tuberous sclerosis complex (TSC) proteins TSC1 and TSC2 regulate protein translation by inhibiting the serine/threonine kinase mTORC1 (for mammalian target of rapamycin complex 1). However, how TSC1 and TSC2 control overall protein synthesis and the translation of specific mRNAs in response to different mitogenic and nutritional stimuli is largely unknown. We show here that serum withdrawal inhibits mTORC1 signaling, causes disassembly of translation initiation complexes, and causes mRNA redistribution from polysomes to subpolysomes in wild-type mouse embryo fibroblasts (MEFs). In

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9

Li, Yong, Ken Inoki, and Kun-Liang Guan. "Biochemical and Functional Characterizations of Small GTPase Rheb and TSC2 GAP Activity." Molecular and Cellular Biology 24, no. 18 (2004): 7965–75. http://dx.doi.org/10.1128/mcb.24.18.7965-7975.2004.

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ABSTRACT Tuberous sclerosis complex (TSC) is a genetic disease caused by a mutation in either the tsc1 or tsc2 tumor suppressor gene. Recent studies have demonstrated that TSC2 displays GAP (GTPase-activating protein) activity specifically towards the small G protein Rheb and inhibits its ability to stimulate the mTOR signaling pathway. Rheb and TSC2 comprise a unique pair of GTPase and GAP, because Rheb has high basal GTP levels and TSC2 does not have the catalytic arginine finger found in Ras-GAP. To investigate the function of TSC2 and Rheb in mTOR signaling, we analyzed the TSC2-stimulated

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10

Matsumoto, Sanae, Amitabha Bandyopadhyay, David J. Kwiatkowski, Umadas Maitra, and Tomohiro Matsumoto. "Role of the Tsc1-Tsc2 Complex in Signaling and Transport Across the Cell Membrane in the Fission Yeast Schizosaccharomyces pombe." Genetics 161, no. 3 (2002): 1053–63. http://dx.doi.org/10.1093/genetics/161.3.1053.

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Abstract Heterozygous inactivation of either human TSC1 or TSC2 causes tuberous sclerosis (TSC), in which development of benign tumors, hamartomas, occurs via a two-hit mechanism. In this study, fission yeast genes homologous to TSC1 and TSC2 were identified, and their protein products were shown to physically interact like the human gene products. Strains lacking tsc1+ or tsc2+ were defective in uptake of nutrients from the environment. An amino acid permease, which is normally positioned on the plasma membrane, aggregated in the cytoplasm or was confined in vacuole-like structures in Δtsc1 a

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Mrozek, Evelyn M., Vineeta Bajaj, Yanan Guo, Izabela A. Malinowska, Jianming Zhang, and David J. Kwiatkowski. "Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer." PLOS ONE 16, no. 4 (2021): e0248380. http://dx.doi.org/10.1371/journal.pone.0248380.

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Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with

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12

Kim, Joseph W., Matthew I. Milowsky, Noah M. Hahn, et al. "Sapanisertib, a dual mTORC1/2 inhibitor, for TSC1- or TSC2-mutated metastatic urothelial carcinoma (mUC)." Journal of Clinical Oncology 39, no. 6_suppl (2021): 431. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.431.

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431 Background: A mammalian target of rapamycin (mTOR) inhibitor, everolimus, showed activity in patients with metastatic urothelial carcinoma (mUC) including an exceptional objective response in a patient with a deleterious TSC1 mutation. Sapanisertib is a potent inhibitor of mTOR complex 1 and 2. Here, we present the data from a phase II study of sapanisertib in patients with TSC1- or TSC2-mutated mUC. Methods: Eligible mUC patients with a TSC1 or TSC2 mutation received sapanisertib 3mg po daily on days 1 through 28 every 28 days. Primary endpoint was the overall response rate. Tumor samples

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Huang, Jingxiang, and Brendan D. Manning. "The TSC1–TSC2 complex: a molecular switchboard controlling cell growth." Biochemical Journal 412, no. 2 (2008): 179–90. http://dx.doi.org/10.1042/bj20080281.

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TSC1 and TSC2 are the tumour-suppressor genes mutated in the tumour syndrome TSC (tuberous sclerosis complex). Their gene products form a complex that has become the focus of many signal transduction researchers. The TSC1–TSC2 (hamartin–tuberin) complex, through its GAP (GTPase-activating protein) activity towards the small G-protein Rheb (Ras homologue enriched in brain), is a critical negative regulator of mTORC1 (mammalian target of rapamycin complex 1). As mTORC1 activity controls anabolic processes to promote cell growth, it is exquisitely sensitive to alterations in cell growth condition

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14

Jaeschke, Anja, Joerg Hartkamp, Masao Saitoh, et al. "Tuberous sclerosis complex tumor suppressor–mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent." Journal of Cell Biology 159, no. 2 (2002): 217–24. http://dx.doi.org/10.1083/jcb.jcb.200206108.

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The evolution of mitogenic pathways has led to the parallel requirement for negative control mechanisms, which prevent aberrant growth and the development of cancer. Principally, such negative control mechanisms are represented by tumor suppressor genes, which normally act to constrain cell proliferation (Macleod, K. 2000. Curr. Opin. Genet. Dev. 10:81–93). Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder, characterized by mutations in either TSC1 or TSC2, whose gene products hamartin (TSC1) and tuberin (TSC2) constitute a putative tumor suppressor complex (TSC1-2; va

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15

Natarajan, Nalini, and Vijay Thiruvenkatam. "An Insight of Scientific Developments in TSC for Better Therapeutic Strategy." Current Topics in Medicinal Chemistry 20, no. 23 (2020): 2080–93. http://dx.doi.org/10.2174/1568026620666200825170355.

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Tuberous sclerosis complex (TSC) is a rare genetic disease, which is characterized by noncancerous tumors in multi-organ systems in the body. Mutations in the TSC1 or TSC2 genes are known to cause the disease. The resultant mutant proteins TSC1 (hamartin) and TSC2 (tuberin) complex evade its normal tumor suppressor function, which leads to abnormal cell growth and proliferation. Both TSC1 and TSC2 are involved in several protein-protein interactions, which play a significant role in maintaining cellular homeostasis. The recent biochemical, genetic, structural biology, clinical and drug discove

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Zarei, Mahsa, Heng Du, Amin H. Nassar, et al. "Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion." Journal of Experimental Medicine 216, no. 11 (2019): 2635–52. http://dx.doi.org/10.1084/jem.20190251.

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Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CD

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17

Lai, Mingqiang, Wenchong Zou, Zelong Han, et al. "Tsc1 regulates tight junction independent of mTORC1." Proceedings of the National Academy of Sciences 118, no. 30 (2021): e2020891118. http://dx.doi.org/10.1073/pnas.2020891118.

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Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor that functions together with Tsc2 to negatively regulate the mechanistic target of rapamycin complex 1 (mTORC1) activity. Here, we show that Tsc1 has a critical role in the tight junction (TJ) formation of epithelium, independent of its role in Tsc2 and mTORC1 regulation. When an epithelial cell establishes contact with neighboring cells, Tsc1, but not Tsc2, migrates from the cytoplasm to junctional membranes, in which it binds myosin 6 to anchor the perijunctional actin cytoskeleton to β-catenin and ZO-1. In its absence, perijunctional

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18

Georgieva, B., M. Koleva, T. Todorov, et al. "Molecular-Genetic Characteristics and Genotype-Phenotype Correlations in Bulgarian Patients with Tuberous Sclerosis Complex." Acta Medica Bulgarica 48, no. 2 (2021): 29–36. http://dx.doi.org/10.2478/amb-2021-0020.

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Abstract Objective The aim of the study was to determine the molecular-genetic characteristics of the autosomal dominant systematic disorder Tuberous Sclerosis Complex (TSC1 and TSC2) in Bulgarian patients and to derive some genotype-phenotype correlations. Material and Methods In total 42 patients/families with suspected clinical diagnosis of TSC were analyzed. We used direct sequencing and MLPA for the TSC1 and TSC2 gene analysis. Results In 38 families (90.5%) we confirmed the suspected clinical diagnosis – 15 with TSC1 (35.7%) and 23 (54.8%) with TSC2. In 4 families (9.5%) pathogenic varia

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Dickson, Mark Andrew, Vinod Ravi, Kristen N. Ganjoo, and Gopa Iyer. "Institutional experience with nab-sirolimus in patients with malignancies harboring TSC1 or TSC2 mutations." Journal of Clinical Oncology 39, no. 15_suppl (2021): 3111. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3111.

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3111 Background: TSC1/ TSC2 genes are tumor suppressors in the mTOR pathway; mutated at low frequency across tumor types (̃1–2%). Retrospective analyses of patients (pts) with mTOR pathway mutations treated with everolimus did not show improved outcomes vs the wild type (Voss et al. Clin Cancer Res 2019. PMID 30327302). In NCT02201212, pts with TSC1/TSC2 mutations treated with everolimus had a 7% (2/30) response rate. In the AMPECT study, pts with advanced PEComa treated with a novel mTOR inhibitor (mTORi), nab-sirolimus ( nab-S, ABI-009), the subset of pts with TSC1/TSC2 mutations had a respo

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Wagner, Andrew J., Vinod Ravi, Kristen N. Ganjoo, et al. "ABI-009 (nab-sirolimus) in advanced malignant perivascular epithelioid cell tumors (PEComa): Preliminary efficacy, safety, and mutational status from AMPECT, an open label phase II registration trial." Journal of Clinical Oncology 37, no. 15_suppl (2019): 11005. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.11005.

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11005 Background: Malignant PEComa is a rare, aggressive sarcoma, with no approved treatment or prior clinical trials. Case reports suggest mTOR activation through mutations or deletions of TSC1 or TSC2 and activity of mTOR inhibitors in this disease. ABI-009 is an albumin-bound mTOR inhibitor with increased tumor uptake. The AMPECT trial is the first prospective study in malignant PEComa. Methods: Eligible patients (pts) with centrally confirmed PEComa receive ABI-009 (100 mg/m2 IV, wkly, 2/3 wks) until progression or unacceptable toxicity. Primary endpoint: ORR by independent review (IR), as

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Sampson, J. R. "TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis." Biochemical Society Transactions 31, no. 3 (2003): 592–96. http://dx.doi.org/10.1042/bst0310592.

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The tuberous sclerosis complex genes TSC1 and TSC2 were first identified by positional cloning strategies in the heritable human disorder tuberous sclerosis. They encode previously unknown proteins, termed hamartin and tuberin respectively, that form a functional complex. The phenotypic manifestations of tuberous sclerosis are extremely diverse and suggest normal roles for TSC1 and TSC2 in regulating the growth, proliferation, migration and differentiation of many cell types. Investigations of TSC1 and TSC2 in a number of model organisms and cell-culture systems have provided new insights into

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Han, Juliette M., and Mustafa Sahin. "TSC1/TSC2 signaling in the CNS." FEBS Letters 585, no. 7 (2011): 973–80. http://dx.doi.org/10.1016/j.febslet.2011.02.001.

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Hernández, Wilfredo, Juan Paz, Fernando Carrasco, et al. "Synthesis and Characterization of New Palladium(II) Complexes with Ligands Derived from Furan-2-carbaldehyde and Benzaldehyde Thiosemicarbazone and their in vitro Cytotoxic Activities against Various Human Tumor Cell Lines." Zeitschrift für Naturforschung B 65, no. 10 (2010): 1271–78. http://dx.doi.org/10.1515/znb-2010-1015.

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With the ligands 4-phenyl-1-(furan-2-carbaldehyde)thiosemicarbazone, HTSC1, (1), 4-phenyl-1- (5´-phenyl-furan-2-carbaldehyde)thiosemicarbazone, HTSC2 (2), o-methoxy-benzaldehydethiosemicarbazone, HTSC3 (3), and o-cyano-benzaldehydethiosemicarbazone, HTSC4 (4), the corresponding palladium(II) complexes, Pd(TSC1)2 (5), Pd(TSC2)2 (6), Pd(TSC3)2 (7), and Pd(TSC4)2 (8) were synthesized and characterized by elemental analysis and spectroscopic techniques. The crystal structure of Pd(TSC3)2 (7) was determined by single-crystal X-ray diffraction. Complex 7 shows a squareplanar geometry, where two depr

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Tomasoni, Romana, and Anna Mondino. "The tuberous sclerosis complex: balancing proliferation and survival." Biochemical Society Transactions 39, no. 2 (2011): 466–71. http://dx.doi.org/10.1042/bst0390466.

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Mutations in genes encoding either hamartin [TSC1 (tuberous sclerosis complex 1)] or tuberin (TSC2) result in a multisystem disorder characterized by the development of benign tumours and hamartomas in several organs. The TSC1 and TSC2 proteins form a complex that lies at the crossroad of many signalling pathways integrating the energy status of the cell with signals induced by nutrients and growth factors. The TSC1/2 complex is a critical negative regulator of mTORC1 [mTOR (mammalian target of rapamycin) complex 1], and by that controls anabolic processes to promote cell growth, proliferation

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Софронова, В. М., Д. А. Петухова, А. Л. Сухомясова, and Н. Р. Максимова. "Tuberous sclerosis in the Republic of Sakha (Yakutia)." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 8(217) (August 31, 2020): 24–26. http://dx.doi.org/10.25557/2073-7998.2020.08.24-26.

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Проведен ретроспективный клинико-генеалогический анализ 20 пациентов с диагнозом туберозный склероз. По результатам молекулярно-генетической диагностики в 3 неродственных якутских и 1 русской семьях выявлены 4 разных патогенных варианта нуклеотидной последовательности в генах TSC1, TSC2. A retrospective clinical and genealogical analysis of 20 patients with a diagnosis of tuberous sclerosis was performed. According to the results of molecular genetics diagnostics, 4 different pathogenic variants of the nucleotide sequence in the TSC1, TSC2 genes were identified in 3 unrelated Yakut and 1 Russi

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Nadiri, Mehdi, Mortaza Raeisi, and Seyed Ali Mousavi Aghdas. "A Novel Mutation in TSC2 Gene: A 34-Year-Old Female with Pulmonary Lymphangioleiomyomatosis with Concomitant Hepatic Lesions." Case Reports in Pulmonology 2018 (2018): 1–3. http://dx.doi.org/10.1155/2018/5928231.

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Tuberous sclerosis complex (TSC) is an autosomal dominant disease resulting from mutation(s) in TSC1 or TSC2 genes. TSC is associated with the formation of hamartomas in the brain, heart, eyes, skin, kidneys, and lymphangioleiomyomatosis (LAM) of the lungs. LAM is almost restricted to women in reproductive age. Different mutations in TSC1 and TSC2 genes have been reported in the literature. Here, we present a female patient with TSC-LAM with a novel mutation in TSC2 gene. The patient also had multiple hepatic angiomyolipomas, which is a relatively less-reported manifestation of the disease. Th

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Voss, Martin Henner, David Chen, Mahtab Marker, et al. "Tumor genomic analysis for 128 renal cell carcinoma (RCC) patients receiving first-line everolimus: Correlation between outcome and mutations status in MTOR, TSC1, and TSC2." Journal of Clinical Oncology 35, no. 6_suppl (2017): 484. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.484.

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484 Background: MTOR inhibitors are standard agents in the management of advanced RCC. Case series have suggested somatic mutations in MTOR, TSC1, and TSC2 may sensitize tumors to everolimus (EVE) [Voss et al., CCR 2014; Kwiatkowski et al., CCR 2016]. We sought to test this hypothesis through next generation sequencing (NGS) of tumors from a large cohort of patients (pts) treated with everolimus (EVE) on the randomized RECORD3 trial of first-line EVE vs. sunitinib. Methods: Somatic mutations were investigated using a custom exon-targeted NGS platform with deep sequence coverage. This analysis

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Cheng, Shun-Yun, Anneliese Malachi, Joris Cipi, et al. "HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies." Biomolecules 11, no. 6 (2021): 871. http://dx.doi.org/10.3390/biom11060871.

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Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein TSC1. Here, we confirm our previous findings by deletion of the other complex protein, namely TSC2, in rod photoreceptors. Similar to deletion of Tsc1, mice with deletion of Tsc2 in rods develop AMD-like pathologies, including accumulation of apolipoproteins, migration of microglia,

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Kövesdi, Erzsébet, Judit Bene, Nikoletta Nagy, Ágnes Horváth, Béla Melegh, and Kinga Hadzsiev. "A nagyobb méretű géndeletiók jelentősége a sclerosis tuberosa diagnosztikájában: az első magyar esetek bemutatása." Orvosi Hetilap 158, no. 30 (2017): 1188–94. http://dx.doi.org/10.1556/650.2017.30789.

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Abstract: Tuberous sclerosis complex is a rare disease with high phenotypic heterogeneity, characterized by the appearance of multiplex hamartomas in the different organs. The disease is inherited by autosomal dominant manner, due to the mutations of two genes: the TSC1 or the TSC2. In this publication we present the cases of two young male and two middle-aged female patients, where pathogenetic differences of TSC1/TSC2 could not be verified by Sanger sequencing. However, multiplex ligation-dependent probe amplification confirmed different sizes of deletions in different regions of the TSC2 ge

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Bernal-MiIzrachi, Ernesto. "TSC1/TSC2 Signaling in Pancreatic β-Cells". Open Endocrinology Journal 4, № 1 (2010): 33–39. http://dx.doi.org/10.2174/1874216501004010033.

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Srivastava, Siddharth, Anna K. Prohl, Benoit Scherrer, et al. "Cerebellar volume as an imaging marker of development in infants with tuberous sclerosis complex." Neurology 90, no. 17 (2018): e1493-e1500. http://dx.doi.org/10.1212/wnl.0000000000005352.

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ObjectiveIn this cohort analysis, we studied 1-year-old infants with tuberous sclerosis complex (TSC), correlating volumes of cerebellar structures with neurodevelopmental measures.MethodsWe analyzed data from a prospective biomarker study in infants with TSC (ClinicalTrials.govNCT01780441). We included participants aged 12 months with an identified mutation of TSC1 or TSC2. Using MRI segmentation performed with the PSTAPLE algorithm, we measured relative volumes (structure volume divided by intracranial contents volume) of the following structures: right/left cerebellar white matter, right/le

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Zhang, Xuchen, and William D. Travis. "Pulmonary Lymphangioleiomyomatosis." Archives of Pathology & Laboratory Medicine 134, no. 12 (2010): 1823–28. http://dx.doi.org/10.5858/2009-0576-rs.1.

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Abstract Lymphangioleiomyomatosis is an uncommon lung disease primarily affecting women of childbearing age. It is characterized by the progressive proliferating and infiltrating smooth musclelike cells (lymphangioleiomyomatosis cells), which lead to the cystic destruction of the lung parenchyma; obstruction of airways, blood vessels, and lymphatics; and loss of pulmonary function. Lymphangioleiomyomatosis cells coexpress smooth muscle markers (such as smooth muscle actin and desmin) and melanocytic markers (such as HMB-45, Melan-A/MART-1, and microphthalmia transcription factor). Dyspnea on e

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Liang, Ning, Chi Zhang, Patricia Dill, et al. "Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex." Journal of Experimental Medicine 211, no. 11 (2014): 2249–63. http://dx.doi.org/10.1084/jem.20140341.

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Genetic studies have shown that the tuberous sclerosis complex (TSC) 1–TSC2–mammalian target of Rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epit

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Çetin, Mecnun, Aysun A. Aydın, and Kamuran Karaman. "Everolimus treatment in a 3-month-old infant with tuberous sclerosis complex cardiac rhabdomyoma, severe left ventricular outflow tract obstruction, and hearing loss." Cardiology in the Young 31, no. 8 (2021): 1359–62. http://dx.doi.org/10.1017/s1047951121000639.

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AbstractTuberous sclerosis complex is a rare multisystem genetic disorder characterised by the growth of numerous tumour-like malformations in many parts of the body including skin, kidneys, brain, lung, eyes, liver, and heart. Mutations in the TSC1 or TSC2 genes have been reported to cause disruption in the TSC1–TSC2 intracellular protein complex, causing over-activation of the mammalian target of rapamycin protein complex. In this study, we present a 3-month-old male infant diagnosed with tuberous sclerosis, bilateral neurosensorial hearing loss, Wolff–Parkinson–White syndrome on electrocard

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Potter, C. J., L. G. Pedraza, H. Huang, and T. Xu. "The tuberous sclerosis complex (TSC) pathway and mechanism of size control." Biochemical Society Transactions 31, no. 3 (2003): 584–86. http://dx.doi.org/10.1042/bst0310584.

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We have identified three groups of growth-constraint genes using mosaic genetic screens in Drosophila melanogaster, including PTEN (phosphatase and tensin homologue deleted on chromosome 10), and the tuberous sclerosis complex (TSC) genes, Tsc1 and Tsc2. Our studies show that all three groups of genes participate in mechanisms that regulate organ and organism size in animals. We propose that mechanisms of organ size control are critical targets for diseases, such as tumorigenesis, which require an increase in tissue size and total mass, and for evolutionary events that alter the size of organi

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Sampson, Julian R. "Therapeutic targeting of mTOR in tuberous sclerosis." Biochemical Society Transactions 37, no. 1 (2009): 259–64. http://dx.doi.org/10.1042/bst0370259.

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Failure in the regulation of mTOR (mammalian target of rapamycin) appears to be critical to the pathogenesis of the inherited disorder tuberous sclerosis and the related lung disease LAM (lymphangioleiomyomatosis). Both diseases are caused by mutations of TSC1 or TSC2 (TSC is tuberous sclerosis complex) that impair GAP (GTPase-activating protein) activity of the TSC1–TSC2 complex for Rheb, leading to inappropriate activity of signalling downstream of mTORC1 (mTOR complex 1). mTOR inhibitors are already used in a variety of clinical settings including as immunosuppressants, anticancer agents an

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Wagner, Andrew J., Izabela Malinowska-Kolodziej, Jeffrey A. Morgan, et al. "Clinical Activity of mTOR Inhibition With Sirolimus in Malignant Perivascular Epithelioid Cell Tumors: Targeting the Pathogenic Activation of mTORC1 in Tumors." Journal of Clinical Oncology 28, no. 5 (2010): 835–40. http://dx.doi.org/10.1200/jco.2009.25.2981.

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PurposePerivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus.Patients and MethodsPatients with advanced PEComa were treated with sirolimus and consented to retrospective col

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Serfontein, J., R. E. R. Nisbet, C. J. Howe, and P. J. de Vries. "Evolution of the TSC1/TSC2-TOR Signaling Pathway." Science Signaling 3, no. 128 (2010): ra49. http://dx.doi.org/10.1126/scisignal.2000803.

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Ramesh, V. "Aspects of tuberous sclerosis complex (TSC) protein function in the brain." Biochemical Society Transactions 31, no. 3 (2003): 579–83. http://dx.doi.org/10.1042/bst0310579.

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Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. Concordant with the tumour-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at both TSC1 and TSC2 loci. LOH has been documented in renal angiomyolipomas, but loss of the wild-type allele in cortical tubers appears very uncommon. We analysed 24 hamartomas from 10 patients for second-hit mutations by several methods, and found no evidence for the inactivation of the second allele i

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Langkau, Nicola, Nicola Martin, Regine Brandt, et al. "TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/TSC2 frequency ratios." European Journal of Pediatrics 161, no. 7 (2002): 393–402. http://dx.doi.org/10.1007/s00431-001-0903-7.

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Bhaskar, Prashanth T., Veronique Nogueira, Krushna C. Patra та ін. "mTORC1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis via Increased Hexokinase II and GLUT1 Expression, Sustained Mcl-1 Expression, and Glycogen Synthase Kinase 3β Inhibition". Molecular and Cellular Biology 29, № 18 (2009): 5136–47. http://dx.doi.org/10.1128/mcb.01946-08.

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ABSTRACT The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1α (HIF1α) abundance, whi

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Chong-Kopera, Huira, Ken Inoki, Yong Li, et al. "TSC1 Stabilizes TSC2 by Inhibiting the Interaction between TSC2 and the HERC1 Ubiquitin Ligase." Journal of Biological Chemistry 281, no. 13 (2006): 8313–16. http://dx.doi.org/10.1074/jbc.c500451200.

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Kapfhamer, David, James McKenna, Caroline J. Yoon, Tracy Murray-Stewart, Robert A. Casero, and Michael J. Gambello. "Ornithine decarboxylase, the rate-limiting enzyme of polyamine synthesis, modifies brain pathology in a mouse model of tuberous sclerosis complex." Human Molecular Genetics 29, no. 14 (2020): 2395–407. http://dx.doi.org/10.1093/hmg/ddaa121.

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Abstract Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder characterized by variable expressivity. TSC results from inactivating variants within the TSC1 or TSC2 genes, leading to constitutive activation of mechanistic target of rapamycin complex 1 signaling. Using a mouse model of TSC (Tsc2-RG) in which the Tsc2 gene is deleted in radial glial precursors and their neuronal and glial descendants, we observed increased ornithine decarboxylase (ODC) enzymatic activity and concentration of its product, putrescine. To test if increased ODC activity and dysre

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Becker, A. J., M. Löbach, H. Klein, et al. "Mutational analysis of TSC1 and TSC2 genes in gangliogliomas." Neuropathology and Applied Neurobiology 27, no. 2 (2001): 105–14. http://dx.doi.org/10.1046/j.0305-1846.2001.00302.x.

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Cheah, Pike-See, Shilpa Prabhakar, David Yellen, et al. "Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin." Science Advances 7, no. 2 (2021): eabb1703. http://dx.doi.org/10.1126/sciadv.abb1703.

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Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins formed a complex to inhibit mTORC1-mediated cell growth and proliferation. Loss of either protein leads to overgrowth lesions in many vital organs. Gene therapy was evaluated in a mouse model of TSC2 using an adeno-associated virus (AAV) vector carrying the complementary for a “condensed” form of human tuberin (cTuberin). Functionality of cTuberin was verified in culture. A mouse model of TSC2 was generated by AAV-Cre recombinase disruption o

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Sofer, Avi, Kui Lei, Cory M. Johannessen, and Leif W. Ellisen. "Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1." Molecular and Cellular Biology 25, no. 14 (2005): 5834–45. http://dx.doi.org/10.1128/mcb.25.14.5834-5845.2005.

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ABSTRACT The tuberous sclerosis tumor suppressors TSC1 and TSC2 regulate the mTOR pathway to control translation and cell growth in response to nutrient and growth factor stimuli. We have recently identified the stress response REDD1 gene as a mediator of tuberous sclerosis complex (TSC)-dependent mTOR regulation by hypoxia. Here, we demonstrate that REDD1 inhibits mTOR function to control cell growth in response to energy stress. Endogenous REDD1 is induced following energy stress, and REDD1 − / − cells are highly defective in dephosphorylation of the key mTOR substrates S6K and 4E-BP1 follow

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Maroto, Pablo, Georgia Anguera, Jose Maria Roldan, et al. "mTOR pathway alterations in chromophobe renal cell carcinoma: Impact on metastasis development and overall survival." Journal of Clinical Oncology 38, no. 6_suppl (2020): 712. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.712.

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712 Background: Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal cancer representing less than 5% of the kidney tumors. Molecular knowledge of this disease is limited, as well as prognostic factors for relapse if localized disease or response in the metastatic setting. Methods: From our database form different Spanish Hospitals, we identified a series of 89 chRCC with a localized stage and 3 patients stage IV at first diagnoses. We performed an in-depth characterization of mTOR pathway alterations, through targeted NGS and immunohistoche

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Li, Shaowei, Fumiko Takeuchi, Ji-an Wang, et al. "MCP-1 overexpressed in tuberous sclerosis lesions acts as a paracrine factor for tumor development." Journal of Experimental Medicine 202, no. 5 (2005): 617–24. http://dx.doi.org/10.1084/jem.20042469.

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Patients with tuberous sclerosis complex (TSC) develop hamartomatous tumors showing loss of function of the tumor suppressor TSC1 (hamartin) or TSC2 (tuberin) and increased angiogenesis, fibrosis, and abundant mononuclear phagocytes. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor–derived cells for altered gene and protein expression. Fibroblast-like cells from 10 angiofibromas and five periungual fibromas produced higher levels of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein than did fibroblasts from the same patient's normal sk

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Flader, M., P. Kurzawa, J. Maldyk, et al. "Papillary thyroid carcinoma in a boy with familial tuberous sclerosis complex attributable to a TSC2 deletion—a case report." Current Oncology 24, no. 5 (2017): 423. http://dx.doi.org/10.3747/co.24.3555.

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Tuberous sclerosis complex (tsc), a phacomatosis, is a rare genetic disease (autosomal dominant; incidence: 1 in 6,800–17,300) associated with mutations in the TSC1 and TSC2 genes, 70% of which are sporadic. The disease causes benign tumours in the brain, kidneys, heart, lungs, skin, and eyes; thyroid lesions are extremely rare.A 13-year-old euthyroid boy with a hereditary form of tsc (del 4730G in TSC2, also seen in 2 sisters and the father) was admitted to hospital with a thyroid nodule. Physical examination revealed a nodular left lobe with increased consistency. Thyroid ultrasonography rev

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Wang, Ji, Harilaos Filippakis, Thomas Hougard, et al. "Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells." Proceedings of the National Academy of Sciences 118, no. 39 (2021): e2101268118. http://dx.doi.org/10.1073/pnas.2101268118.

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Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either TSC1 or TSC2. Cytokine profiling of TSC2-deficient LAM patient–derived cells revealed striking up-regulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed up-regulation of IL-6 transcription and secretion compared to wild-type cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced

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