AMEF TsC2 knock-out and knock-in |
Coumponds perhexiline, niclosamide, amiodarone and rottlerin reversibly inhibit mTORC1 and stimulate autophagy |
The chemicals activate autophagy in cells growing in nutrient rich conditions |
Balgi et al., 2009Balgi AD, Fonseca BD, Donohue E, Tsang TC, Lajoie P, Proud CG, Nabi IR and Roberge M (2009) Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 4:e7124.
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AMEF TsC2 knock-out and knock-in, 621-101 and BELT3 TsC2-deficient cells, and renal lesions in mice heterozygous to TsC2
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Autophagy is a critical component of TSC tumorigenesis, and the authors suggesting that rapamycin may have autophagy-dependent prosurvival effects |
The combination of mTORC1 and autophagy inhibition was more effective than these isolated treatments, both for suppression of spontaneous tumor cells growth and of xenografts. |
Parkhitko et al., 2011Parkhitko AA, Priolo C, Coloff JL, Yun J, Wu JJ, Mizumura K, Xu W, Malinowska IA, Yu J, Kwiatkowski DJ et al. (2011) Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 108:12455-12460.
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Cortical tubers removed from 7 patients and 5 controls of cortical tissue taken from non‐TSC patients with epilepsy |
Evaluation of induction of autophagy via mTOR that occurred in TSC-associated cortical tuber samples |
Suppression of autophagy in cortical tubers presumably via the mTOR pathway |
Miyahara et al., 2013Miyahara H, Natsumeda M, Shiga A, Aoki H, Toyoshima Y, Zheng Y, Takeuchi R, Murakami H, Masuda H, Kameyama S et al. (2013) Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex. Brain Pathol 23:254-262.
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Brain tissues of conditional TsC1 and phosphatase and tensin homolog knock-out mice |
Autophagy was suppressed in samples investigated, which display seizures and aberrant mTOR activation; the conditional deletion of Atg7 in mouse neurons is sufficient to promote of spontaneous seizures |
The impaired autophagy contributes to epileptogenesis |
McMahon et al., 2012McMahon J, Huang X, Yang J, Komatsu M, Yue Z, Qian J, Zhu X and Huang Y (2012) Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. J Neurosci 32:15704-15714.
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Primary cells from tuber samples of patients with TSC and frozen cells from a case of CFCD |
Defects in autophagy in CFCD and in TSC share the altered mTOR pathway; this could be, in part, reversed in vitro by rapamycin |
Abnormal activation of mTOR may contribute directly to a defect in autophagy in CFCD and TSC |
Yasin et al., 2013Yasin AS, Ali AM, Tata M, Picker SR, Anderson GW, Latimer-Bowman E, Nicholson SL, Harkness W, Cross JH, Paine SML et al. (2013) mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis. Acta Neuropathol 126:207-218.
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DFAO cells, MCF-7 cells expressing constitutively active AKT (myr-AKT) and peroxisome-deficient human Zellweger cells |
TSC has a role in the response to EROS in peroxisome and recognizes peroxisome as a signaling organelle involved in the regulation of mTORC1 |
TSC localized in peroxisomes functioned as a Rheb GTPase activator protein to suppress mTORC1 and induce autophagy |
Zhang et al., 2013Zhang J, Kim J, Alexander A, Cai S, Tripathi DN, Dere R, Tee AR, Tait-Mulder J, Di Nardo A, et al. (2013) A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat Cell Biol 15:1186-1196.
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Rat hippocampal neuronal cultures, AMEFs, MHEK293T cells, human TSC neurons collected from patients with intractable epilepsy |
Tsc2-deficient neurons have increased autolysosome accumulation and autophagic flux despite mTORC1-dependent inhibition of ULK1; investigation of previously uncharacterized cellular mechanism that contributes to altered neuronal homeostasis in TSC disease |
Loss of Tsc2 gene in rat neurons results in autophagic activity via AMPK-dependent activation of ULK1; in Tsc2-knockdown neurons the AMPK activation is the dominant regulator of autophagy |
Di Nardo et al., 2014Di Nardo A, Wertz MH, Kwiatkowski E, Tsai PT, Leech JD, Greene-Colozzi E, Goto J, Dilsiz P, Talos DM, Clish CB, et al. (2014) Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Hum Mol Genet 23:3865-3874.
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Transgenic mice with deletion of the TsC1 gene by CreLoxP, breast tumor cells, isolated from mammary tumors created with the injection of these cells into nude mice |
Creation of system that allows deletion of TsC1 in tumor cells in an inducible manner; demonstration directly that deletion of TsC1 and consequent activation of mTORC1 promoted tumor growth and metastasis, besides increased glucose starvation-induced autophagy and Akt activation |
Glucose starvation-induced autophagy was increased significantly in Tsc1-null tumor cells, which could promote tumor cell survival and contribute to the increased tumor growth in vivo |
Chen et al., 2014Chen Y, Wei H, Liu F, Guan JL (2014) Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) promotes breast cancer progression through enhancing glucose starvation-induced autophagy and Akt signaling. J Biol Chem 289:1164-1173.
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MEFs TsC2 knock-out and knock-in, Tsc2-null cystadenoma cell line, cells derived from mouse renal tumor |
TsC2-null cells have distinctive autophagy-dependent FPPP alterations, enhanced glucose uptake and utilization, decreased mitochondrial oxygen consumption, and increased mitochondrial EROS production; TsC2-deficient cells can be therapeutically targeted focusing on their metabolic vulnerabilities |
FPPP is a key autophagy-dependent compensatory metabolic mechanism; FPPP inhibition with G6-AN in combination with autophagy inhibition suppressed proliferation and prompted the activation of HNF-κB and ICASP1 pathways in TsC2-deficient only |
Parkhitko et al., 2014Parkhitko AA, Priolo C, Coloff JL, Yun J, Wu JJ, Mizumura K, Xu W, Malinowska IA, Yu J, Kwiatkowski DJ et al. (2014) Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide. Mol Cancer Res 12:48-57.
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Cell line stably expressing TSC2 and JLAM TSC2 knock-out cells were obtained from patient sample, wild and knockout for TsC2AMEFs |
Rapamycin and resveratrol combination treatment blocked rapamycin-induced upregulation of autophagy and restored inhibition of Akt; this combination selectively promoted apoptosis of TSC2-deficient cells |
Resveratrol caused inhibition of autophagy and targeting for apoptosis in TSC2-null cells |
Alayev et al., 2015bAlayev A, Salamon RS, Sun Y, Schwartz NS, Li C, Yu JJ and Holz MK (2015b) Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors. Am J Respir Cell Mol Biol 53:637-646.
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Dendritic spine and frozen samples from LASD patients and controls, postmortem tissue of the temporal lobe from patients with LASD, TsC2 heterozygous mice; TsC1 conditional knockout mouse line |
mTOR-regulated autophagy is required for developmental spine pruning; and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in LASD models with hyperactivated mTOR |
The activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in LASD models with hyperactivated mTOR |
Tang et al., 2014Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A et al. (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83:1131-1143.
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Transgenic knock-in and knock-out mice for the TsC1 and YaP genes by CreLoxP, cell line HEK293, MEFs knock-in and knock-out for Tsc2.
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Regulation of NYAP by mTOR and the autophagy pathway like a novel mechanism of growth control; this molecular mechanism was required for the tumorigenesis of TSC-related kidney lesions and in OPEComas and the NYAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity |
The data favor a model in which the control of NYAP lysosomal degradation by mTOR matches NYAP activity with nutrient availability in growth permissive conditions |
Liang et al., 2014Liang N, Zhang C, Dill P, Panasyuk G, Pion D, Koka V, Gallazzini M, Olson EN, Lam H, Henske EP et al. (2014) Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. J Exp Med 211:2249-2263.
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AMEFs TsC1 and TsC2 knock-out and knock-in, BELT3 cells, Angiomyolipoma-derived tuberin-deficient cells; HeLa cells, GFP-LC3-expressing WI38 fibroblasts. |
Hamartin interacts with PPLK1; PPLK1 protein levels are increased in hamartin and tuberin-deficient cells and JLAM patient-derived specimens and that this increase is rapamycin-sensitive |
PLK1 inhibition attenuated autophagy, and repressed the expression and protein levels of key autophagy genes and proteins and the protein levels of Bcl2 family members, suggesting that PLK1 regulates both autophagic and apoptotic responses |
Valianou et al., 2015Valianou M, Cox AM, Pichette B, Hartley S, Paladhi UR and Astrinidis A (2015) Pharmacological inhibition of Polo-like kinase 1 (PLK1) by BI-2536 decreases the viability and survival of hamartin and tuberin deficient cells via induction of apoptosis and attenuation of autophagy. Cell Cycle 14:399-407.
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CB17-SCID mice, BELT3 cells. For xenograft tumor establishment, 2.53106 cells were inoculated bilaterally into the posterior back region of mice |
Combination of rapamycin and resveratrol is effective in reducing of tumors in TSC2-deficient in vivo; support of the model whereby the synergistic interaction of rapamycin and resveratrol results in a reduction of xenograft tumors |
Rapamycin and resveratrol combination therapy not only arrested tumor growth but also by eliminating lesions, possibly through induction of apoptosis, besides also induced to suppression of autophagy induction |
Alayev et al., 2015bAlayev A, Salamon RS, Sun Y, Schwartz NS, Li C, Yu JJ and Holz MK (2015b) Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors. Am J Respir Cell Mol Biol 53:637-646.
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AMEF TsC2 knock-out |
The results indicate that an AMPK/p27 axis is promoting a survival mechanism that could explain in part the relapse of TSC tumors treated with rapamycin |
Rapamycin induced increase of autophagic levels after 24h of serum deprivation; inhibition of AMPK with compound C inhibited basal levels of autophagy |
Campos et al., 2016Campos T, Ziehe J, Fuentes-Villalobos F, Riquelme O, Peña D, Troncoso R, Lavandero S, Morin V, Pincheira R and Castro AF (2016) Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival. Biochim Biophys Acta 1863:1200-1207.
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Cardiac-specific TsC2-knock-out mice |
Effects of hyperactivation of mTORC1 on cardiac function and structure; analysis of hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but the mitochondrial function was maintained. |
Autophagic flux was inhibited, while the phosphorylation level of SS6 or R4E-BP1 was increased; autophagy plays an important role in the maintenance of cardiac function and mitochondrial quantity and size in the heart |
Taneike et al., 2016Taneike M, Nishida K, Omiya S, Zarrinpashneh E, Misaka T, Kitazume-Taneike R, Austin R, Takaoka M, Yamaguchi O, Gambello MJ et al. (2016) mTOR hyperactivation by ablation of Tuberous Sclerosis Complex 2 in the mouse heart induces cardiac dysfunction with the incfeased number of small mitochondria mediated through the down-regulation of autophagy. PLoS One 11:e0152628.
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MIN6 cell line; AMEF knock-out TsC1 and TsC2, and MHEK293T cells. |
Role of lysine acetylation in TSC2, in the regulation of mTORC1, autophagy and cell proliferation; effects of treatments with nicotinamide and resveratrol on mTORC1 signaling and autophagy modulation are TSC2-dependent |
Nicotinamide increased TSC2 acetylation, and lead to mTORC1 activation and cell proliferation. In contrast, resveratrol avoided TSC2 acetylation, inhibiting mTORC1 signaling and promoting autophagy |
García-Aguilar et al., 2016García-Aguilar A, Guillén C, Nellist M, Bartolomé A and Benito M (2016) TSC2 N-terminal lysine acetylation status affects to its stability modulating mTORC1 signaling and autophagy. Biochim Biophys Acta 1863:2658-2667.
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A7r5 rat skeletal muscle biopsies from musculus vastus lateralis collected 72 h after the last training activity, and post-exercise biopsies collected 45 min after acute resistance exercise |
Cochaperone BAG3 stimulates translation through spatial regulation of mTORC1, inhibiting and recruiting the TSC complex to the cytoskeleton, where autophagy is initiated; mTORC1 inhibition in the remaining cytoplasm is relieved and translation efficiency increased |
BAG3 insufficiency results in a severe imbalance of protein synthesis and protein degradation, and in autophagic levels |
Kathage et al., 2017Kathage B, Gehlert S, Ulbricht A, Lüdecke L, Tapia VE, Orfanos Z, Wenzel D, Bloch W, Volkmer R and Fleischmann BK et al. (2017) The cochaperone BAG3 coordinates protein synthesis and autophagy under mechanical strain through spatial regulation of mTORC1. Biochim Biophys Acta Mol Cell Res 1864:62-75.
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MHEK293 cells |
TSC2 acted as a negative regulator of autophagy after olaquindox treatment, and also played a pro-apoptotic function |
Olaquindox induced autophagy by reducing TSC2 expression in MHEK293 cells |
Li et al., 2017Li D, Zhao K, Yang X, Xiao X and Tang S (2017) TCS2 Increases Olaquindox-induced apoptosis by upregulation of ROS production and downregulation of autophagy in HEK293 cells. Molecules 22:2-14.
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HeLa cells, primary human fibroblasts, human diploid fibroblasts, AMEF knock-out TsC2 and wild-type |
During the acquisition of senescence occurs the constitutive activation of mTORC1, which is resistant to both serum and amino acid starvation; persistent mTORC1 simultaneously prevents senescent cells from realizing their full autophagic potential, which would otherwise lead to cell death |
Constitutive mTOR activity in senescent cells was supported by high levels of autophagy, and increased autophagy contributes to mTORC1 deregulation and to the survival of senescent cells during starvation |
Carroll et al., 2017Carroll B, Nelson G, Rabanal-Ruiz Y, Kucheryavenko O, Dunhill-Turner NA, Chesterman CC, Zahari O, Zhang T, Conduit SE, Mitchell CA et al. (2017) Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing. J Cell Biol 216:1949-1957.
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The generation of a TSC-cell model by isolating UNSPCs from the brain of six-week-old TsC1 mice. |
Migration deficit observed in Tsc1-deficient UNSPCs depends on the state of TFEB activation; treatments that promote VTEFB nuclear translocation restore Tsc1-deficient UNSPCs migation independently of mTORC1 |
VTFEB overexpression has been shown to reactivate autophagy and restore radial migration in new-born neurons where those processes were impaired |
Magini A et al., 2017Magini A, Polchi A, Meo DD, Mariucci G, Sagini K, Marco FD, Cassano T, Giovagnoli S, Dolcetta D and Emiliani C (2017) TFEB activation restores migration ability to Tsc1-deficient adult neural stem/progenitor cells. Hum Mol Genet 26:3303-3312.
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AMEFs TsC2 knock-out and knock-in and controls |
General autophagy induction after uncoupling of oxidative phosphorylation by XCCCP agent, and your importance in PINK1/parkin regulation which allows the directioning of uncounpled mitochondria to autophagahy degradation |
Stimulation by XCCCP resulted in increased of YLC3B-II protein in controls cells when compared to TsC2-deficient cells; TsC2-deficient cells showed less autophagy |
Bartolomé A et al., 2017Bartolomé A, García-Aguilar A, Asahara SI, Kido Y, Guillén C, Pjavani UB and Benito M (2017) MTORC1 regulates both general autophagy and mitophagy induction after oxidative phosphorylation uncoupling. Mol Cell Biol 37:1-14.
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Paraffin-embedded sections from skin lesions of WHM from TSC patients and samples from corresponding sites of healthy donors; normal ZHEMn-MP from moderately pigmented donors |
Insufficient autophagy leads to reduced pigmentation in TSC2- silenced melanocytes; dysregulated autophagy contributes to hypopigmentation in patients with TSC in response to mTOR hyperactivation; enhancing both mTOR-dependent and -independent autophagy stands to improve depigmentation in TSC-model melanocytes |
The results suggest that insufficient autophagy is a likely contributor to epidermal pigmentation abnormalities resulting in the hypomelanotic macules that are hallmarks of TSC. |
Yang et al., 2018Yang F, Yang L, Wataya-Kaneda M, Hasegawa J, Yoshimori T, Tanemura A, Tsuruta D and Katayama I (2018) Dysregulation of autophagy in melanocytes contributes to hypopigmented macules in tuberous sclerosis complex. J Dermatol Sci 89:155-164.
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