Deptor: not only a mTOR inhibitor

Catena, Valeria; Fanciulli, Maurizio

doi:10.1186/s13046-016-0484-y

Cited by 75 publications

(70 citation statements)

References 53 publications

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“…3), which is an important component of MTOR complexes and is a natural negative regulator of MTOR kinase activity. Dysregulation of MTOR activity associated with DEPTOR reduction has been widely implicated in disease pathogenesis, including cancer and Alzheimer's disease development (25,32). DEPTOR reduction at the mRNA level was observed by lamin B1 knockdown ( Fig.…”

Section: Discussionmentioning

confidence: 93%

“…Lamin B1 knockdown-mediated DEPTOR reduction is responsible for MTOR activation and accelerated cellular senescence in HBEC DEPTOR constitutes a part of MTOR complexes and has an essential inhibitory role in the kinase activity of MTOR (25). We examined the involvement of DEPTOR in lamin B1 knockdownmediated MTOR activation.…”

Section: Effect Of Lamin B1 Reduction On Cellular Senescence Mtor Acmentioning

confidence: 99%

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Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis

Saito

Araya

Ito

et al. 2019

The Journal of Immunology

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Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)–induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)–treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain–containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1β–mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

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Section: Discussionmentioning

confidence: 93%

Section: Effect Of Lamin B1 Reduction On Cellular Senescence Mtor Acmentioning

confidence: 99%

Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis

Saito

Araya

Ito

et al. 2019

The Journal of Immunology

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“…The complete role of DEPTOR within the cells has not yet been fully elucidated, although the involvement of DEPTOR in several biological processes, such as cell growth, apoptosis, and autophagy, has been reported [15]. A potential role of DEPTOR as a tumor suppressor or as an oncogene, depending on cell context, has also been described.…”

Section: Introductionmentioning

confidence: 99%

DEPTOR maintains plasma cell differentiation and favorably affects prognosis in multiple myeloma

et al. 2017

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BackgroundThe B cell maturation process involves multiple steps, which are controlled by relevant pathways and transcription factors. The understanding of the final stages of plasma cell (PC) differentiation could provide new insights for therapeutic strategies in multiple myeloma (MM). Here, we explore the role of DEPTOR, an mTOR inhibitor, in the terminal differentiation of myeloma cells, and its potential impact on patient survival.MethodsThe expression level of DEPTOR in MM cell lines and B cell populations was measured by real-time RT-PCR, and/or Western blot analysis. DEPTOR protein level in MM patients was quantified by capillary electrophoresis immunoassay. RNA interference was used to downregulate DEPTOR in MM cell lines.ResultsDEPTOR knockdown in H929 and MM1S cell lines induced dedifferentiation of myeloma cells, as demonstrated by the upregulation of PAX5 and BCL6, the downregulation of IRF4, and a clear reduction in cell size and endoplasmic reticulum mass. This effect seemed to be independent of mTOR signaling, since mTOR substrates were not affected by DEPTOR knockdown. Additionally, the potential for DEPTOR to be deregulated in MM by particular miRNAs was investigated. The ectopic expression of miR-135b and miR-642a in myeloma cell lines substantially diminished DEPTOR protein levels, and caused dedifferentiation of myeloma cells. Interestingly, the level of expression of DEPTOR protein in myeloma patients was highly variable, the highest levels being associated with longer progression-free survival.ConclusionsOur results demonstrate for the first time that DEPTOR expression is required to maintain myeloma cell differentiation and that high level of its expression are associated with better outcome.Primary samples used in this study correspond to patients entered into GEM2010 trial (registered at www.clinicaltrials.gov as #NCT01237249, 4 November 2010).Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0461-8) contains supplementary material, which is available to authorized users.

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“…An important side note is that DEPTOR levels are often low in many tumors, leading to upregulation of mTOR. 62 Substances that either increase DEPTOR or enhance and regulate DEPTOR binding could theoretically be important in inhibiting cancers.…”

Section: Resveratrolmentioning

confidence: 99%

Botanical Medicine and Phytochemicals in Healthy Aging and Longevity—Part 1

Lucius

2020

Alternative and Complementary Therapies

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Deptor: not only a mTOR inhibitor

Cited by 75 publications

References 53 publications

Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis

Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis

DEPTOR maintains plasma cell differentiation and favorably affects prognosis in multiple myeloma

Botanical Medicine and Phytochemicals in Healthy Aging and Longevity—Part 1

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