Che‐1‐induced inhibition of
            <scp>mTOR</scp>
            pathway enables stress‐induced autophagy

Desantis, Agata; Bruno, Tiziana; Catena, Valeria; Nicola, Francesca De; Goeman, Frauke; Iezzi, Simona; Socolovschi, Cristina; Ponzoni, Maurilio; Bossi, Gianluca; Verde, Federico; Rosa, Francesca La; Ricciardi, Maria Rosaria; Lesma, Elena; Meo, Paolo D Onorio De; Castrignanò, Tiziana; Petrucci, Maria Teresa; Pisani, Francesco; Chesi, Marta; Bergsagel, P. Leif; Floridi, Aristide; Tonon, Giovanni; Passananti, Claudio; Blandino, Giovanni; Fanciulli, Maurizio

doi:10.15252/embj.201489920

Cited by 71 publications

(99 citation statements)

References 65 publications

(116 reference statements)

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“…It is certainly possible that, with study of a larger cohort, there will be a statistically significant difference. However, a recent study (32) demonstrates an additional inducer of DEPTOR expression, CHE-1. As the presence of CHE-1 may not necessarily correlate with the IgH translocation sub-group, future studies to identify predictive markers of sensitivity to anti-DEPTOR therapy should investigate DEPTOR RNA or protein expression rather than simply FISH determined MM classification.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells

et al. 2016

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DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Over-expression of DEPTOR specifically occurs in a model of multiple myeloma (MM). Its silencing in MM cells is sufficient to induce cytotoxicity, suggesting DEPTOR is a potential therapeutic target. mTORC1 paralysis protects MM cells against DEPTOR silencing, implicating mTORC1 in DEPTOR’s critical role in MM cell viability. Building on this foundation, we interrogated a small molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR-mTOR binding in human myeloma cells with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell cycle arrest in MM cell lines and prevented outgrowth of human MM cells in immunodeficient mice. In vitro cytotoxicity against MM cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary MM cells while normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in MM and suggest an effective strategy of preventing binding of DEPTOR to mTOR.

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Section: Discussionmentioning

confidence: 99%

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells

et al. 2016

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“…However, we did not explore the molecular mechanisms responsible for this reduction. REDD1 transcriptional activation can be mediated by different transcription factors such as p63 (18), HIF-1α (20), ATF4 (40), Che-1 (41), or PLZF (42) among others. On the other hand, there is less understanding of REDD1 inhibitory mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Suppression of REDD1 in osteoarthritis cartilage, a novel mechanism for dysregulated mTOR signaling and defective autophagy

Álvarez-García

Olmer

Akagi

et al. 2016

Osteoarthritis and Cartilage

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Objective Aging is a main risk factor for the development of osteoarthritis (OA) and the molecular mechanisms underlying the aging-related changes in articular cartilage include increased mammalian target of rapamycin (mTOR) signaling and defective autophagy. REDD1 is an endogenous inhibitor of mTOR that regulates cellular stress responses. In this study we measured REDD1 expression in normal, aged and OA cartilage and assessed REDD1 function in human and mouse articular chondrocytes. Methods REDD1 expression was analyzed in human and mouse articular cartilage by qPCR, western blotting, and immunohistochemistry. For functional studies, REDD1 and TXNIP knockdown or overexpression was performed in chondrocytes in the presence or absence of rapamycin and chloroquine, and mTOR signaling and autophagy were measured by western blotting. REDD1/TXNIP protein interaction was assessed by co-immunoprecipitation experiments. Results Human and mouse cartilage from normal knee joints expressed high levels of REDD1. REDD1 expression was significantly reduced in aged and OA cartilage. In cultured chondrocytes, REDD1 knockdown increased whereas REDD1 overexpression decreased mTOR signaling. In addition, REDD1 activated autophagy by an mTOR independent mechanism that involved protein/protein interaction with TXNIP. The REDD1/TXNIP complex was required for autophagy activation in chondrocytes. Conclusion The present study shows that REDD1 is highly expressed in normal human articular cartilage and reduced during aging and OA. REDD1 in human chondrocytes negatively regulates mTOR activity and is essential for autophagy activation. Reduced REDD1 expression thus represents a novel mechanism for the increased mTOR activation and defective autophagy observed in OA.

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“…Induction of REDD1 is an important mechanism to overcome stress-induced impairment of cellular functions. REDD1 expression enables stress-induced autophagy by inhibition of mTOR signalling [11,47]. Autophagy contributes to stress-clearance by controlled elimination of damaged or harmful cellular components [48].…”

Section: Discussionmentioning

confidence: 99%

“…One important mediator of the cellular stress response is the mTOR inhibitor Regulated in Development and DNA Damage Responses 1 (REDD1, DIG2, DDIT4, RTP801). Several stressors such as energy depletion [6], ER stress [7,8], hypoxia [9,10], DNA damage by irradiation [11] and chemicals [12] induce the expression of REDD1. Additionally REDD1 expression is increased by pharmacological derivatives of cortisol such as dexamethasone [8,13] and by insulin [14].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Jessica

Bongartz

Klepsch

et al. 2016

Cellular Signalling

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Abstract:Interleukin 6 is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by interleukin 6 (IL-6) is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.

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Che‐1‐induced inhibition of mTOR pathway enables stress‐induced autophagy

Cited by 71 publications

References 65 publications

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells

Suppression of REDD1 in osteoarthritis cartilage, a novel mechanism for dysregulated mTOR signaling and defective autophagy

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

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