Mechanism of action of rapamycin: New insights into the regulation of G1-phase progression in eukaryotic cells

Wiederrecht, Gregory; Sabers, Candace J.; Brunn, Gregory J.; Martin, Mary M.; Dumont, Francis J.; Abraham, Robert T.

doi:10.1007/978-1-4615-1809-9_5

Cited by 158 publications

(111 citation statements)

References 126 publications

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“…The Akt/mTOR pathway has been shown to regulate cell-cycle progression, as inhibition of this pathway can result in G1 cell-cycle arrest (Wiederrecht et al, 1995;Hentges et al, 2001). We have previously shown that U-251 cells treated with PMA for 24 h resulted in a striking increase in PKC-Z protein levels (Hussaini et al, 2000).…”

Section: H-thymidine Uptakementioning

confidence: 95%

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

et al. 2004

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Section: H-thymidine Uptakementioning

confidence: 95%

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

et al. 2004

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“…We tested whether leptin affects the expression of the protein kinase B (AKT) and its downstream energy-sensing mTOR pathway (34)(35)(36). We found that FACS-sorted MOG -specific CD4 + T cells from ob/ob mice had lower levels of phosphorylation of both AKT and S6, which is downstream of the mTOR pathway (Fig.…”

Section: Autoreactive Cd4mentioning

confidence: 99%

Leptin Modulates the Survival of Autoreactive CD4+ T Cells through the Nutrient/Energy-Sensing Mammalian Target of Rapamycin Signaling Pathway

Galgani

Procaccini

Rosa

et al. 2010

The Journal of Immunology

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Chronic inflammation can associate with autoreactive immune responses, including CD4+ T cell responses to self-Ags. In this paper, we show that the adipocyte-derived proinflammatory hormone leptin can affect the survival and proliferation of autoreactive CD4+ T cells in experimental autoimmune encephalomyelitis, an animal model of human multiple sclerosis. We found that myelin olygodendrocyte glycoprotein peptide 35–55 (MOG35–55)-specific CD4+ T cells from C57BL/6J wild-type mice could not transfer experimental autoimmune encephalomyelitis into leptin-deficient ob/ob mice. Such a finding was associated with a reduced proliferation of the transferred MOG35–55-reactive CD4+ T cells, which had a reduced degradation of the cyclin-dependent kinase inhibitor p27kip1 and ERK1/2 phosphorylation. The transferred cells displayed reduced Th1/Th17 responses and reduced delayed-type hypersensitivity. Moreover, MOG35–55-reactive CD4+ T cells in ob/ob mice underwent apoptosis that associated with a downmodulation of Bcl-2. Similar results were observed in transgenic AND-TCR- mice carrying a TCR specific for the pigeon cytochrome c 88–104 peptide. These molecular events reveal a reduced activity of the nutrient/energy-sensing AKT/mammalian target of rapamycin pathway, which can be restored in vivo by exogenous leptin replacement. These results may help to explain a link between chronic inflammation and autoimmune T cell reactivity.

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“…The FK506-binding protein-12-rapamycin complex then binds to and inhibits the kinase activities of the mammalian target of rapamycin serine/threonine protein kinase, the activation of which is essential for protein synthesis and cell cycle progression. The presence of rapamycin during T cell activation blocks T cell cycle progression in the G 1 phase, resulting in the induction of tolerance (3,4). Because of its immunosuppressive properties, rapamycin is currently used to prevent graft rejection (5).…”

mentioning

confidence: 99%

Rapamycin-Mediated Enrichment of T Cells with Regulatory Activity in Stimulated CD4+ T Cell Cultures Is Not Due to the Selective Expansion of Naturally Occurring Regulatory T Cells but to the Induction of Regulatory Functions in Conventional CD4+ T Cells

Valmori

Tosello

Souleimanian

et al. 2006

The Journal of Immunology

178

125

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Rapamycin is an immunosuppressive drug currently used in different clinical settings. Although the capacity of rapamycin to inhibit the mammalian target of rapamycin serine/threonine protein kinase and therefore T cell cycle progression is well known, its effects are complex and not completely understood. It has been reported recently that TCR-mediated stimulation of murine CD4+ T cells in the presence of rapamycin results in increased proportions of CD4+ T cells with suppressive functions, suggesting that the drug may also exert its immunosuppressive activity by promoting the selective expansion of naturally occurring CD4+ regulatory T cells (Treg). In this study, we show that stimulation of human circulating CD4+ T cells in the presence of rapamycin results indeed in highly increased suppressor activity. By assessing the effect of rapamycin on the growth of nonregulatory and Treg populations of defined differentiation stages purified ex vivo from circulating CD4+ T cells, we could demonstrate that this phenomenon is not due to a selective expansion of naturally occurring Tregs, but to the capacity of rapamycin to induce, upon TCR-mediated stimulation, suppressor functions in conventional CD4+ T cells. This condition, however, is temporary and reversible as it is dependent upon the continuous presence of rapamycin.

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Mechanism of action of rapamycin: New insights into the regulation of G1-phase progression in eukaryotic cells

Cited by 158 publications

References 126 publications

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

Leptin Modulates the Survival of Autoreactive CD4+ T Cells through the Nutrient/Energy-Sensing Mammalian Target of Rapamycin Signaling Pathway

Rapamycin-Mediated Enrichment of T Cells with Regulatory Activity in Stimulated CD4+ T Cell Cultures Is Not Due to the Selective Expansion of Naturally Occurring Regulatory T Cells but to the Induction of Regulatory Functions in Conventional CD4+ T Cells

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