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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
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
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.
1 Communities
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24 MeSH Terms
Zebrafish model of tuberous sclerosis complex reveals cell-autonomous and non-cell-autonomous functions of mutant tuberin.
Kim SH, Speirs CK, Solnica-Krezel L, Ess KC
(2011) Dis Model Mech 4: 255-67
MeSH Terms: Animals, Brain, Cell Size, Codon, Nonsense, Disease Models, Animal, Embryo, Nonmammalian, Gene Expression Regulation, Developmental, Hepatocytes, Humans, Liver, Mutant Proteins, Neurons, Sirolimus, Transcription Factors, Tuberous Sclerosis, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins, Zebrafish
Show Abstract · Added September 24, 2013
Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by mutations in either the TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes. Patients with TSC have hamartomas in various organs throughout the whole body, most notably in the brain, skin, eye, heart, kidney and lung. To study the development of hamartomas, we generated a zebrafish model of TSC featuring a nonsense mutation (vu242) in the tsc2 gene. This tsc2(vu242) allele encodes a truncated Tuberin protein lacking the GAP domain, which is required for inhibition of Rheb and of the TOR kinase within TORC1. We show that tsc2(vu242) is a recessive larval-lethal mutation that causes increased cell size in the brain and liver. Greatly elevated TORC1 signaling is observed in tsc2(vu242/vu242) homozygous zebrafish, and is moderately increased in tsc2(vu242/+) heterozygotes. Forebrain neurons are poorly organized in tsc2(vu242/vu242) homozygous mutants, which have extensive gray and white matter disorganization and ectopically positioned cells. Genetic mosaic analyses demonstrate that tsc2 limits TORC1 signaling in a cell-autonomous manner. However, in chimeric animals, tsc2(vu242/vu242) mutant cells also mislocalize wild-type host cells in the forebrain in a non-cell-autonomous manner. These results demonstrate a highly conserved role of tsc2 in zebrafish and establish a new animal model for studies of TSC. The finding of a non-cell-autonomous function of mutant cells might help explain the formation of brain hamartomas and cortical malformations in human TSC.
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18 MeSH Terms
Phospholipase D1 is an effector of Rheb in the mTOR pathway.
Sun Y, Fang Y, Yoon MS, Zhang C, Roccio M, Zwartkruis FJ, Armstrong M, Brown HA, Chen J
(2008) Proc Natl Acad Sci U S A 105: 8286-91
MeSH Terms: Cell Line, Humans, Monomeric GTP-Binding Proteins, Neuropeptides, Phospholipase D, Protein Kinases, RNA Interference, RNA, Small Nuclear, Ras Homolog Enriched in Brain Protein, Signal Transduction, TOR Serine-Threonine Kinases, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins
Show Abstract · Added March 21, 2013
The mammalian target of rapamycin (mTOR) assembles a signaling network essential for the regulation of cell growth, which has emerged as a major target of anticancer therapies. The tuberous sclerosis complex 1 and 2 (TSC1/2) proteins and their target, the small GTPase Rheb, constitute a key regulatory pathway upstream of mTOR. Phospholipase D (PLD) and its product phosphatidic acid are also upstream regulators of the mitogenic mTOR signaling. However, how the TSC/Rheb and PLD pathways interact or integrate in the rapamycin-sensitive signaling network has not been examined before. Here, we find that PLD1, but not PLD2, is required for Rheb activation of the mTOR pathway, as demonstrated by the effects of RNAi. The overexpression of Rheb activates PLD1 in cells in the absence of mitogenic stimulation, and the knockdown of Rheb impairs serum stimulation of PLD activation. Furthermore, the overexpression of TSC2 suppresses PLD1 activation, whereas the knockdown or deletion of TSC2 leads to elevated basal activity of PLD. Consistent with a TSC-Rheb-PLD signaling cascade, AMPK and PI3K, both established regulators of TSC2, appear to lie upstream of PLD as revealed by the effects of pharmacological inhibitors, and serum activation of PLD is also dependent on amino acid sufficiency. Finally, Rheb binds and activates PLD1 in vitro in a GTP-dependent manner, strongly suggesting that PLD1 is a bona fide effector for Rheb. Hence, our findings reveal an unexpected interaction between two cascades in the mTOR signaling pathways and open up additional possibilities for targeting this important growth-regulating network for the development of anticancer drugs.
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14 MeSH Terms