ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer

Harwood, Franklin C.; Geltink, Ramon I. Klein; O’Hara, Brendan P.; Cardone, Monica; Janke, Laura J.; Finkelstein, David; Entin, Igor; Paul, Leena; Houghton, Peter J.; Grosveld, Gerard

doi:10.1126/sciadv.aar3938

Cited by 88 publications

(127 citation statements)

References 62 publications

(101 reference statements)

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“…mTOR is atypical serine/threonine protein kinase from the phosphoinositide 3-kinase (PI3K)-related kinase family, which maintains the balance between anabolic and catabolic processes in response to a variety of physiological and pathological conditions [66]. mTOR pathway regulates myriad biological processes such as protein synthesis, proliferation, autophagy, metabolism, cell survival, and others through distinct protein complexes including mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2) and mTOR complex 3 (mTORC3) [66,67]. The most intensively studied of all mTOR complexes is undoubtedly mTORC1.…”

Section: Discussionmentioning

confidence: 99%

mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

Madrakhimov

Yang

Kim

et al. 2020

Preprint

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Background: Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in diabetic retinopathy. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of diabetic retinopathy was investigated in 1-month-diabetic mice treated with phlorizin or rapamycin. The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin or MHY1485. Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis.Results: mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker – cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer (GCL), as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion: Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway.

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Section: Discussionmentioning

confidence: 99%

mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

Madrakhimov

Yang

Kim

et al. 2020

Preprint

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“…9 A serine/threonine kinase, mTOR exists as a component member of three separate complexes, mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), 9 and the recently identified mTOR complex 3 (mTORC3). 10 Acute rapamycin treatment has been shown to inhibit mTORC1 only, with mTORC2 11 and mTORC3 insensitive to its effects. 10 Because of its integral role in various signaling pathways, 9 mTOR dysfunction has been linked to a number of disease states, including ocular disorders.…”

mentioning

confidence: 99%

“…10 Acute rapamycin treatment has been shown to inhibit mTORC1 only, with mTORC2 11 and mTORC3 insensitive to its effects. 10 Because of its integral role in various signaling pathways, 9 mTOR dysfunction has been linked to a number of disease states, including ocular disorders. 12 Previous studies have demonstrated the ability of rapamycin to reduce retinal neovascularization in vitro 13 and in vivo 14 by inhibiting mTORC1, which acts through hypoxia inducible factor 1α (HIF-1α) to downregulate VEGF.…”

mentioning

confidence: 99%

“…9 Unlike first-generation inhibitors, consisting of rapamycin and its structural analogues, called rapalogs, that only affect mTORC1, 11 these second-generation inhibitors were found to effectively block mTORC3 activity as well. 10 However, we utilized CAPSID (Convenient Application Program for siRNA Design), a program developed in-house, to design a novel short hairpin RNA (shRNA) specifically targeting mTOR. 16 By doing so, RNA interference is used to directly downregulate mTOR activity, rather than the inhibition being effected in a roundabout manner.…”

mentioning

confidence: 99%

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Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Lee

Chang²,

Kim

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Citation: Lee SHS, Chang H, Kim JH, et al. Inhibition of mTOR via an AAV-Delivered shRNA tested in a rat OIR model as a potential antiangiogenic gene therapy. Invest Ophthalmol Vis Sci. 2020;61(2):45. https://doi.org/10.1167/iovs.61.2.45 PURPOSE.Recent studies have shown that inhibitors of the mechanistic target of rapamycin (mTOR) play important roles in proliferating endothelial cells within the retinal vasculature. Here we explore the effects of inhibiting mTOR as a potential gene therapeutic against pathological retinal angiogenesis in a rat model of oxygen-induced retinopathy (OIR). METHODS.Sprague-Dawley pups were used to generate the OIR model, with a recombinant adeno-associated virus expressing an shRNA (rAAV2-shmTOR-GFP) being administered via intravitreal injection on returning the rats to normoxia, with appropriate controls. Immunohistochemistry and TUNEL assays, as well as fluorescein angiography, were performed on transverse retinal sections and flat mounts, respectively, to determine the in vivo effects of mTOR inhibition. RESULTS.Compared with normal control rats, as well as OIR model animals that were either untreated (20.95 ± 6.85), mock-treated (14.50 ± 2.47), or injected with a control short hairpin RNA (shRNA)-containing virus vector (16.64 ± 4.92), rAAV2-shmTOR-GFP (4.28 ± 2.86, P = 0.00103) treatment resulted in dramatically reduced neovascularization as a percentage of total retinal area. These results mirrored quantifications of retinal avascular area and vessel tortuosity, with rAAV2-shmTOR-GFP exhibiting significantly greater therapeutic efficacy than the other treatments. The virus vector was additionally shown to reduce inflammatory cell infiltration into retinal tissue and possess antiapoptotic properties, both these processes having been implicated in the pathophysiology of angiogenic retinal disorders. CONCLUSIONS.Taken together, these results demonstrate the strong promise of rAAV2-shmTOR-GFP as an effective and convenient gene therapy for the treatment of neovascular retinal diseases.

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“…Due to its translocation function, the overexpression of ETV7 has been associated with tumorigenic transformation and anti-apoptosis by blocking Mys-induced apoptosis pathway (26)(27)(28). Furthermore, there are growing experimental evidences showing that ETV7 also plays a significant role in mTOR signaling pathway by assembling mTOR3 complex, which can stimulate cell proliferation and is not sensitive to rapamycin, a common anti-tumor agent, unlike mTOR1/2 (29). So the depletion of ETV7 may cause the inactivation of mTOR3, thus leading to tumor cell death after treatment.…”

Section: Precise Stratification Of Tcga-lihc Samples Based On Metabolmentioning

confidence: 99%

Integrated regulatory-metabolic network model reveals critical mechanism and potential targets for Hepatocellular Carcinoma

Yi-zhou¹,

Zhang²,

Yang³

et al. 2020

Preprint

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ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer

Abstract: A novel mTOR complex assembled by the ETS transcription factor ETV7 contributes to rapamycin resistance in cancer.

Cited by 88 publications

References 62 publications

mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

Integrated regulatory-metabolic network model reveals critical mechanism and potential targets for Hepatocellular Carcinoma

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