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Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming.
Armstrong LC, Westlake G, Snow JP, Cawthon B, Armour E, Bowman AB, Ess KC
(2017) Hum Mol Genet 26: 4629-4641
MeSH Terms: Adolescent, Adult, Alleles, Cellular Reprogramming, Child, Child, Preschool, Female, Fibroblasts, Genes, p53, Heterozygote, Humans, Induced Pluripotent Stem Cells, Infant, Loss of Heterozygosity, Male, Mutation, RNA, Small Interfering, Signal Transduction, TOR Serine-Threonine Kinases, Tuberous Sclerosis, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Show Abstract · Added April 11, 2018
Tuberous sclerosis complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity. To study aberrations of early development in TSC, we generated induced pluripotent stem cells using dermal fibroblasts obtained from patients with TSC. During validation, we found that stem cells generated from TSC patients had a very high rate of integration of the reprogramming plasmid containing a shRNA against TP53. We also found that loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53 levels and impair stem cell reprogramming. Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene dosage. These results support important contributions of TSC2 heterozygous and homozygous mutant cells to the pathogenesis of TSC and the important role of p53 during reprogramming.
© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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24 MeSH Terms
miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway.
Riquelme I, Tapia O, Leal P, Sandoval A, Varga MG, Letelier P, Buchegger K, Bizama C, Espinoza JA, Peek RM, Araya JC, Roa JC
(2016) Cell Oncol (Dordr) 39: 23-33
MeSH Terms: Base Sequence, Cell Death, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Class I Phosphatidylinositol 3-Kinases, Down-Regulation, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Humans, MicroRNAs, Models, Biological, Molecular Sequence Data, Neoplasm Invasiveness, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction, Stomach Neoplasms, TOR Serine-Threonine Kinases, Transfection, Tuberous Sclerosis Complex 1 Protein, Tumor Stem Cell Assay, Tumor Suppressor Proteins
Show Abstract · Added February 5, 2016
BACKGROUND - Gastric cancer (GC) is a deadly malignancy worldwide. In the past, it has been shown that cellular signaling pathway alterations play a crucial role in the development of GC. In particular, deregulation of the PI3K/AKT/mTOR pathway seems to affect multiple GC functions including growth, proliferation, metabolism, motility and angiogenesis. Targeting alterations in this pathway by microRNAs (miRNAs) represents a potential therapeutic strategy, especially in inhibitor-resistant tumors. The objective of this study was to evaluate the expression of 3 pre-selected miRNAs, miR-101-2, miR-125b-2 and miR-451a, in a series of primary GC tissues and matched non-GC tissues and in several GC-derived cell lines, and to subsequently evaluate the functional role of these miRNAs.
METHODS - Twenty-five primary GC samples, 25 matched non-GC samples and 3 GC-derived cell lines, i.e., AGS, MKN28 and MKN45, were included in this study. miRNA and target gene expression levels were assessed by quantitative RT-PCR and western blotting, respectively. Subsequently, cell viability, clone formation, cell death, migration and invasion assays were performed on AGS cells.
RESULTS - miR-101-2, miR-125b-2 and miR-451a were found to be down-regulated in the primary GC tissues and the GC-derived cell lines tested. MiRNA mimic transfections significantly reduced cell viability and colony formation, increased cell death and reduced cell migration and invasion in AGS cells. We also found that exogenous expression of miR-101-2, miR-125b-2 and miR-451a decreased the expression of their putative targets MTOR, PIK3CB and TSC1, respectively.
CONCLUSIONS - Our expression analyses and in vitro functional assays suggest that miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in primary GCs as well as in GC-derived AGS cells.
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24 MeSH Terms
Dynamic tubers in tuberous sclerosis complex: A window for intervention?
Ess KC, Chugani HT
(2015) Neurology 85: 1530-1
MeSH Terms: Brain, Female, Humans, Male, Tuberous Sclerosis, White Matter
Added February 16, 2016
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6 MeSH Terms
Evaluation of diffusion kurtosis imaging in ex vivo hypomyelinated mouse brains.
Kelm ND, West KL, Carson RP, Gochberg DF, Ess KC, Does MD
(2016) Neuroimage 124: 612-626
MeSH Terms: Animals, Axons, Brain, Carrier Proteins, Diffusion, Diffusion Tensor Imaging, Disease Models, Animal, Magnetic Resonance Imaging, Mice, Mice, Knockout, Myelin Sheath, Rapamycin-Insensitive Companion of mTOR Protein, Tuberous Sclerosis, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins, White Matter
Show Abstract · Added February 16, 2016
Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and DKI-derived white matter tract integrity metrics (WMTI) were experimentally evaluated ex vivo through comparisons to histological measurements and established magnetic resonance imaging (MRI) measures of myelin in two knockout mouse models with varying degrees of hypomyelination. DKI metrics of mean and radial kurtosis were found to be better indicators of myelin content than conventional DTI metrics. The biophysical WMTI model based on the DKI framework reported on axon water fraction with good accuracy in cases with near normal axon density, but did not provide additional specificity to myelination. Overall, DKI provided additional information regarding white matter microstructure compared with DTI, making it an attractive method for future assessments of white matter development and pathology.
Copyright © 2015 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist.
de Vries PJ, Whittemore VH, Leclezio L, Byars AW, Dunn D, Ess KC, Hook D, King BH, Sahin M, Jansen A
(2015) Pediatr Neurol 52: 25-35
MeSH Terms: Adolescent, Adult, Brain Diseases, Checklist, Child, Child, Preschool, Humans, Infant, Mental Disorders, Pilot Projects, Terminology as Topic, Tuberous Sclerosis
Show Abstract · Added February 16, 2016
BACKGROUND - Tuberous sclerosis complex is a multisystem genetic disorder with a range of physical manifestations that require evaluation, surveillance, and management. Individuals with tuberous sclerosis complex also have a range of behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial difficulties. These may represent the greatest burden of the disease. Around 90% of individuals with tuberous sclerosis complex will have some of these difficulties during their lifetime, yet only about 20% ever receive evaluation and treatment. The Neuropsychiatry Panel at the 2012 Tuberous Sclerosis Complex International Consensus Conference expressed concern about the significant "treatment gap" and about confusion regarding terminology relating to the biopsychosocial difficulties associated with tuberous sclerosis complex.
METHODS - The Tuberous Sclerosis Complex Neuropsychiatry Panel coined the term TAND-tuberous sclerosis complex-associated neuropsychiatric disorders-to bring together these multidimensional manifestations of the disorder, and recommended annual screening for TAND. In addition, the Panel agreed to develop a TAND Checklist as a guide for screening.
RESULTS - Here, we present an outline of the conceptualization of TAND, rationale for the structure of the TAND Checklist, and include the full US English version of the TAND Checklist.
CONCLUSION - We hope that the unified term TAND and the TAND Checklist will raise awareness of the importance of tuberous sclerosis complex-associated neuropsychiatric disorders and of the major burden of disease associated with it, provide a shared language and a simple tool to describe and evaluate the different levels of TAND, alert clinical teams and families or individuals of the importance of screening, assessment, and treatment of TAND, and provide a shared framework for future studies of tuberous sclerosis complex-associated neuropsychiatric disorders.
Copyright © 2015 Elsevier Inc. All rights reserved.
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12 MeSH Terms
PIP4kγ is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation.
Mackey AM, Sarkes DA, Bettencourt I, Asara JM, Rameh LE
(2014) Sci Signal 7: ra104
MeSH Terms: Animals, Cytoplasm, Fibroblasts, HEK293 Cells, HeLa Cells, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes, Mutation, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Signal Transduction, TOR Serine-Threonine Kinases, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins
Show Abstract · Added November 26, 2018
Phosphatidylinositol-5-phosphate 4-kinases (PIP4ks) are a family of lipid kinases that specifically use phosphatidylinositol 5-monophosphate (PI-5-P) as a substrate to synthesize phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Suppression of PIP4k function in Drosophila results in smaller cells and reduced target of rapamycin complex 1 (TORC1) signaling. We showed that the γ isoform of PIP4k stimulated signaling through mammalian TORC1 (mTORC1). Knockdown of PIP4kγ reduced cell mass in cells in which mTORC1 is constitutively activated by Tsc2 deficiency. In Tsc2 null cells, mTORC1 activation was partially independent of amino acids or glucose and glutamine. PIP4kγ knockdown inhibited the nutrient-independent activation of mTORC1 in Tsc2 knockdown cells and reduced basal mTORC1 signaling in wild-type cells. PIP4kγ was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kγ was enriched in light microsomal vesicles, whereas the unphosphorylated form was enriched in heavy microsomal vesicles associated with the Golgi. Furthermore, basal mTORC1 signaling was enhanced by overexpression of unphosphorylated wild-type PIP4kγ or a phosphorylation-defective mutant and decreased by overexpression of a phosphorylation-mimetic mutant. Together, these results demonstrate that PIP4kγ and mTORC1 interact in a self-regulated feedback loop to maintain low and tightly regulated mTORC1 activation during starvation.
Copyright © 2014, American Association for the Advancement of Science.
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16 MeSH Terms
Heterozygous inactivation of tsc2 enhances tumorigenesis in p53 mutant zebrafish.
Kim SH, Kowalski ML, Carson RP, Bridges LR, Ess KC
(2013) Dis Model Mech 6: 925-33
MeSH Terms: Abdominal Neoplasms, Alleles, Animals, Blood Vessels, Cell Transformation, Neoplastic, Gene Silencing, Heterozygote, Intracellular Signaling Peptides and Proteins, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Multiprotein Complexes, Mutation, Neovascularization, Pathologic, Proto-Oncogene Proteins c-akt, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Up-Regulation, Vascular Endothelial Growth Factor A, Zebrafish, Zebrafish Proteins
Show Abstract · Added September 24, 2013
Tuberous sclerosis complex (TSC) is a multi-organ disorder caused by mutations of the TSC1 or TSC2 genes. A key function of these genes is to inhibit mTORC1 (mechanistic target of rapamycin complex 1) kinase signaling. Cells deficient for TSC1 or TSC2 have increased mTORC1 signaling and give rise to benign tumors, although, as a rule, true malignancies are rarely seen. In contrast, other disorders with increased mTOR signaling typically have overt malignancies. A better understanding of genetic mechanisms that govern the transformation of benign cells to malignant ones is crucial to understand cancer pathogenesis. We generated a zebrafish model of TSC and cancer progression by placing a heterozygous mutation of the tsc2 gene in a p53 mutant background. Unlike tsc2 heterozygous mutant zebrafish, which never exhibited cancers, compound tsc2;p53 mutants had malignant tumors in multiple organs. Tumorigenesis was enhanced compared with p53 mutant zebrafish. p53 mutants also had increased mTORC1 signaling that was further enhanced in tsc2;p53 compound mutants. We found increased expression of Hif1-α, Hif2-α and Vegf-c in tsc2;p53 compound mutant zebrafish compared with p53 mutant zebrafish. Expression of these proteins probably underlies the increased angiogenesis seen in compound mutant zebrafish compared with p53 mutants and might further drive cancer progression. Treatment of p53 and compound mutant zebrafish with the mTORC1 inhibitor rapamycin caused rapid shrinkage of tumor size and decreased caliber of tumor-associated blood vessels. This is the first report using an animal model to show interactions between tsc2, mTORC1 and p53 during tumorigenesis. These results might explain why individuals with TSC rarely have malignant tumors, but also suggest that cancer arising in individuals without TSC might be influenced by the status of TSC1 and/or TSC2 mutations and be potentially treatable with mTORC1 inhibitors.
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24 MeSH Terms
Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells.
Fu C, Ess KC
(2013) Genesis 51: 284-92
MeSH Terms: Alleles, Animals, Brain, Exons, Founder Effect, Gene Deletion, Gene Knock-In Techniques, Homozygote, Mice, Mice, Transgenic, Neural Stem Cells, Protein Structure, Tertiary, TOR Serine-Threonine Kinases, Tuberous Sclerosis Complex 1 Protein, Tumor Suppressor Proteins
Show Abstract · Added December 2, 2013
Tuberous sclerosis complex (TSC) is a genetic disease characterized by multiorgan benign tumors as well as neurological manifestations. Epilepsy and autism are two of the more prevalent neurological complications and are usually severe. TSC is caused by mutations in either the TSC1 (encodes hamartin) or the TSC2 (encodes tuberin) genes with TSC2 mutations being associated with worse outcomes. Tuberin contains a highly conserved GTPase-activating protein (GAP) domain that indirectly inhibits mammalian target of rapamycin complex 1 (mTORC1). mTORC1 dysregulation is currently thought to cause much of the pathogenesis in TSC but mTORC1-independent mechanisms may also contribute. We generated a novel conditional allele of Tsc2 by flanking exons 36 and 37 with loxP sites. Mice homozygous for this knock-in Tsc2 allele are viable and fertile with normal appearing growth and development. Exposure to Cre recombinase then creates an in-frame deletion involving critical residues of the GAP domain. Homozygous conditional mutant mice generated using Emx1(Cre) have increased cortical mTORC1 signaling, severe developmental brain anomalies, seizures, and die within 3 weeks. We found that the normal levels of the mutant Tsc2 mRNA, though GAP-deficient tuberin protein, appear unstable and rapidly degraded. This novel animal model will allow further study of tuberin function including the requirement of the GAP domain for protein stability.
Copyright © 2013 Wiley Periodicals, Inc.
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15 MeSH Terms
Deletion of Rictor in neural progenitor cells reveals contributions of mTORC2 signaling to tuberous sclerosis complex.
Carson RP, Fu C, Winzenburger P, Ess KC
(2013) Hum Mol Genet 22: 140-52
MeSH Terms: Animals, Anxiety, Behavior, Animal, Blotting, Western, Carrier Proteins, Electroencephalography, Fluorescent Antibody Technique, Gene Deletion, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Knockout, Multiprotein Complexes, Rapamycin-Insensitive Companion of mTOR Protein, Seizures, Signal Transduction, Sleep, TOR Serine-Threonine Kinases, Tuberous Sclerosis
Show Abstract · Added August 25, 2013
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with severe neurologic manifestations, including epilepsy, autism, anxiety and attention deficit hyperactivity disorder. TSC is caused by the loss of either the TSC1 or TSC2 genes that normally regulate the mammalian target of rapamycin (mTOR) kinase. mTOR exists within two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Loss of either TSC gene leads to increased mTORC1 but decreased mTORC2 signaling. As the contribution of decreased mTORC2 signaling to neural development and homeostasis has not been well studied, we generated a conditional knockout (CKO) of Rictor, a key component of mTORC2. mTORC2 signaling is impaired in the brain, whereas mTORC1 signaling is unchanged. Rictor CKO mice have small brains and bodies, normal lifespan and are fertile. Cortical layering is normal, but neurons are smaller than those in control brains. Seizures were not observed, although excessive slow activity was seen on electroencephalography. Rictor CKO mice are hyperactive and have reduced anxiety-like behavior. Finally, there is decreased white matter and increased levels of monoamine neurotransmitters in the cerebral cortex. Loss of mTORC2 signaling in the cortex independent of mTORC1 can disrupt normal brain development and function and may contribute to some of the neurologic manifestations seen in TSC.
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18 MeSH Terms
Cystogenesis and elongated primary cilia in Tsc1-deficient distal convoluted tubules.
Armour EA, Carson RP, Ess KC
(2012) Am J Physiol Renal Physiol 303: F584-92
MeSH Terms: Aging, Animals, Carrier Proteins, Cilia, DNA, Gene Expression Regulation, Kidney Diseases, Kidney Tubules, Distal, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Multiprotein Complexes, Proteins, Rapamycin-Insensitive Companion of mTOR Protein, Signal Transduction, TOR Serine-Threonine Kinases, Trans-Activators, Transcription Factors, Tuberous Sclerosis Complex 1 Protein, Tumor Suppressor Proteins
Show Abstract · Added August 25, 2013
Tuberous sclerosis complex (TSC) is a multiorgan hamartomatous disease caused by loss of function mutations of either the TSC1 or TSC2 genes. Neurological symptoms of TSC predominate in younger patients, but renal pathologies are a serious aspect of the disease in older children and adults. To study TSC pathogenesis in the kidney, we inactivated the mouse Tsc1 gene in the distal convoluted tubules (DCT). At young ages, Tsc1 conditional knockout (CKO) mice have enlarged kidneys and mild cystogenesis with increased mammalian target of rapamycin complex (mTORC)1 but decreased mTORC2 signaling. Treatment with the mTORC1 inhibitor rapamycin reduces kidney size and cystogenesis. Rapamycin withdrawal led to massive cystogenesis involving both distal as well as proximal tubules. To assess the contribution of decreased mTORC2 signaling in kidney pathogenesis, we also generated Rictor CKO mice. These animals did not have any detectable kidney pathology. Finally, we examined primary cilia in the DCT. Cilia were longer in Tsc1 CKO mice, and rapamycin treatment returned cilia length to normal. Rictor CKO mice had normal cilia in the DCT. Overall, our findings suggest that loss of the Tsc1 gene in the DCT is sufficient for renal cystogenesis. This cytogenesis appears to be mTORC1 but not mTORC2 dependent. Intriguingly, the mechanism may be cell autonomous as well as non-cell autonomous and possibly involves the length and function of primary cilia.
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20 MeSH Terms