mTOR: A Cellular Regulator Interface in Health and Disease

Boutouja, Fahd; Stiehm, Christian M.; Platta, Harald W.

doi:10.3390/cells8010018

Cited by 119 publications

(111 citation statements)

References 213 publications

(237 reference statements)

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“…Indeed, elevated mTOR activity has been reported in IBD patients, and mTOR inhibitors have been shown to be effective in IBD . Loss of function of autophagy can lead to misregulation of ROS, resulting in defects in mucin accumulation . In support, we showed that ROS and the autophagy inducer such as mTOR inhibitor induced mucin secretion in IECs, but an autophagy inhibitor or ROS scavenger inhibited mucin production in IECs.…”

Section: Discussionsupporting

confidence: 67%

Glutathione S‐transferase theta 1 protects against colitis through goblet cell differentiation via interleukin‐22

et al. 2020

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The enzyme glutathione S‐transferase theta 1 (GSTT1) is involved in detoxifying chemicals, including reactive oxygen species (ROS). Here, we provide a significant insight into the role of GSTT1 in inflammatory bowel disease (IBD). We identified decreased expression of GSTT1 in inflamed colons from IBD patients compared to controls. We intrarectally or intraperitoneally delivered Gstt1 gene to mice with dextran sodium sulfate (DSS)‐induced colitis and noted attenuation of colitis through gene transfer of Gstt1 via an IL‐22 dependent pathway. Downregulation of GSTT1 by pathogen‐associated molecular patterns (PAMPs) of microbes reduced innate defense responses and goblet cell differentiation. The GSTT1 mutation in intestinal epithelial cells (IECs) and IBD patients decreased its dimerization, which was connected to insufficient phosphorylation of signal transducer and activator of transcription‐3 and p38/mitogen‐activated protein kinase by their common activator, IL‐22. GSTT1 ameliorated colitis and contributed as a modulator of goblet cells through sensing pathogens and host immune responses. Its mutations are linked to chronic intestinal inflammation due to its insufficient dimerization. Our results provide new insights into GSTT1 mutations that are linked to chronic intestinal inflammation due to its insufficient dimerization and their functional consequences in IBDs.

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Section: Discussionsupporting

confidence: 67%

Glutathione S‐transferase theta 1 protects against colitis through goblet cell differentiation via interleukin‐22

et al. 2020

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“…3.1 mTORC1 [97,99] The Mammalian target of rapamycin complex I (mTORC1) controls growth and metabolism in response to nutrients, energy and redox status. The mTORC1 complex consists of the mTOR kinase, the core subunits Raptor and mLST8, and the PRAS40 and DEPTOR inhibitory subunits.…”

Section: Type 2 Diabetes -Mtorc1-centric Unifying Paradigmmentioning

confidence: 99%

“…In line with that, TSC1,2 knockout and constitutive RagA.GTP result in constitutive activation of mTORC1 under fasting conditions. mTORC1 controls growth and metabolism by phosphorylating and/or affecting its downstream targets S6K1, 4EBP, CRTC2, lipin, ATF4, HIF1a, PPARg, PPARa, ULK1, TFEB and others [97,99]. Phosphorylation of S6K1 and 4EBP results in ribosome biogenesis and in initiating CAP-dependent mRNA translation.…”

Section: Type 2 Diabetes -Mtorc1-centric Unifying Paradigmmentioning

confidence: 99%

“…Some mTORC1 activities in the T2D context are transduced by interacting with mTORC2. The mTORC2 complex consists of the mTOR kinase, mLST8, Rictor (instead of mTORC1 Raptor) mSin1, Deptor and Protor [97,99]. mTORC2 phosphorylates and activates Akt(Ser473), the AGC protein kinases (PKA, PKG, PKC) and Serum and glucocorticoid kinase (SGK).…”

Section: Type 2 Diabetes -Mtorc1-centric Unifying Paradigmmentioning

confidence: 99%

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Type 2 diabetes – unmet need, unresolved pathogenesis, mTORC1-centric paradigm

Bar‐Tana

2020

Rev Endocr Metab Disord

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The current paradigm of type 2 diabetes (T2D) is gluco-centric, being exclusively categorized by glycemic characteristics. The gluco-centric paradigm views hyperglycemia as the primary target, being driven by resistance to insulin combined with progressive beta cells failure, and considers glycemic control its ultimate treatment goal. Most importantly, the gluco-centric paradigm considers the non-glycemic diseases associated with T2D, e.g., obesity, dyslipidemia, hypertension, macrovascular disease, microvascular disease and fatty liver as 'risk factors' and/or 'outcomes' and/or 'comorbidities', rather than primary inherent disease aspects of T2D. That is in spite of their high prevalence (60-90%) and major role in profiling T2D morbidity and mortality. Moreover, the gluco-centric paradigm fails to realize that the non-glycemic diseases of T2D are driven by insulin and, except for glycemic control, response to insulin in T2D is essentially the rule rather than the exception. Failure of the glucocentric paradigm to offer an exhaustive unifying view of the glycemic and non-glycemic diseases of T2D may have contributed to T2D being still an unmet need. An mTORC1-centric paradigm maintains that hyperactive mTORC1 drives the glycemic and non-glycemic disease aspects of T2D. Hyperactive mTORC1 is proposed to act as double-edged agent, namely, to interfere with glycemic control by disrupting the insulin receptor-Akt transduction pathway, while concomitantly driving the non-glycemic diseases of T2D. The mTORC1-centric paradigm may offer a novel perspective for T2D in terms of pathogenesis, clinical focus and treatment strategy.

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“…Both mTORC1 and mTORC2 contains mLST8/GβL and DEPTOR, while mTORC1 also contains PRAS40 and Raptor, and mTORC2-specific components include rapamycin-insensitive component of mTOR (Rictor), mSin1, and Protor-1/2 [40,92]. mTOR complexes regulate growth, metabolism, autophagy cell death and mRNA translation [93,94].…”

Section: Dr and Mtormentioning

confidence: 99%

Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction

Jiang

Yan

Feng

et al. 2019

Cells

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Dietary restriction (DR), which is defined as a reduction of particular or total nutrient intake without causing malnutrition, has been proved to be a robust way to extend both lifespan and health-span in various species from yeast to mammal. However, the molecular mechanisms by which DR confers benefits on longevity were not yet fully elucidated. The forkhead box O transcription factors (FOXOs), identified as downstream regulators of the insulin/IGF-1 signaling pathway, control the expression of many genes regulating crucial biological processes such as metabolic homeostasis, redox balance, stress response and cell viability and proliferation. The activity of FOXOs is also mediated by AMP-activated protein kinase (AMPK), sirtuins and the mammalian target of rapamycin (mTOR). Therefore, the FOXO-related pathways form a complex network critical for coordinating a response to environmental fluctuations in order to maintain cellular homeostasis and to support physiological aging. In this review, we will focus on the role of FOXOs in different DR interventions. As different DR regimens or calorie (energy) restriction mimetics (CRMs) can elicit both distinct and overlapped DR-related signaling pathways, the benefits of DR may be maximized by combining diverse forms of interventions. In addition, a better understanding of the precise role of FOXOs in different mechanistic aspects of DR response would provide clear cellular and molecular insights on DR-induced increase of lifespan and health-span.

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mTOR: A Cellular Regulator Interface in Health and Disease

Cited by 119 publications

References 213 publications

Glutathione S‐transferase theta 1 protects against colitis through goblet cell differentiation via interleukin‐22

Glutathione S‐transferase theta 1 protects against colitis through goblet cell differentiation via interleukin‐22

Type 2 diabetes – unmet need, unresolved pathogenesis, mTORC1-centric paradigm

Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction

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