Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression

Woltman, Andrea M.; Kooij, Sandra W. van der; Coffer, Paul J.; Offringa, Rienk; Daha, Mohamed R.; Kooten, Cees van

doi:10.1182/blood-2002-06-1688

Cited by 136 publications

(120 citation statements)

References 52 publications

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“…Other reports describe p27 as antiapoptotic gene (St Croix et al, 1996;Eymin et al, 1999). Therefore, this suggests that the survival effects of p27 kip1 are cell-type specific and may be mediated by p27 effects on antiapoptotic protein expression (Eymin et al, 1999;Woltman et al, 2003). Whether similar molecular mechanisms underlie the increase in TRAIL resistance upon silencing of p27 kip1 remains to be further investigated.…”

Section: Discussionmentioning

confidence: 94%

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

et al. 2008

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To define novel pathways that regulate susceptibility to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in non-small cell lung cancer (NSCLC), we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant NSCLC cells, levels of different miRs are increased, and in particular, miR-221 and -222. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. Indeed, transfection with anti-miR-221 and -222 rendered CALU-1-resistant cells sensitive to TRAIL. Conversely, H460-sensitive cells treated with -221 and -222 pre-miRs become resistant to TRAIL. miR-221 and -222 target the 3 0 -UTR of Kit and p27 kip1 mRNAs, but interfere with TRAIL signaling mainly through p27 kip1 . In conclusion, we show that high expression levels of miR-221 and -222 are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets or diagnostic tool for TRAIL resistance in NSCLC.

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Section: Discussionmentioning

confidence: 94%

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

et al. 2008

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“…In this context, Li et al 56 found a role for 4E-BP1 in the translational control of proteins critical for cell survival. We observed in this study the suppressed phosphorylation of 4E-BP1 by treatment of Ocl with rapamycin, which may account for part of the apoptotic 58 reported that GM-CSF-mediated survival of dendritic cells indeed depends on PI3K/mTOR signaling and MCL-1. These findings along with those presented here suggest a broader involvement of mTOR in cell survival within the monocyte/macrophage-derived cell lineages.…”

Section: Discussionmentioning

confidence: 53%

M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

et al. 2003

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Multinucleated bone-resorbing osteoclasts (Ocl) are cells of hematopoietic origin that play a major role in osteoporosis pathophysiology. Ocl survival and activity require M-CSF and RANK ligand (RANKL). M-CSF signals to Akt, while RANKL, like TNFa, activates NF-jB. We show here that although these are separate pathways in the Ocl, signaling of all three cytokines converges on mammalian target of rapamycin (mTOR) as part of their antiapoptotic action. Accordingly, rapamycin blocks M-CSF-and RANKL-dependent Ocl survival inducing apoptosis, and suppresses in vitro bone resorption proportional to the reduction in Ocl number. The cytokine signaling intermediates for mTOR/ribosomal protein S6 kinase (S6K) activation include phosphatidylinositol-3 kinase, Akt, Erks and geranylgeranylated proteins. Inhibitors of these intermediates suppress cytokine activation of S6K and induce Ocl apoptosis. mTOR regulates protein translation acting via S6K, 4E-BP1 and S6. We find that inhibition of translation by other mechanisms also induces Ocl apoptosis, demonstrating that Ocl survival is highly sensitive to continuous de novo protein synthesis. This study thus identifies mTOR/S6K as an essential signaling pathway engaged in the stimulation of cell survival in osteoclasts.

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“…Monocyte-derived DCs (MD-DCs) were generated as described (22,23). Briefly, PBMC were separated by density gradient centrifugation from leukocyte concentrates obtained from healthy volunteers.…”

Section: Cell Culturementioning

confidence: 99%

Rac1 Negatively Regulates Lipopolysaccharide-Induced IL-23 p19 Expression in Human Macrophages and Dendritic Cells and NF-κB p65 trans Activation Plays a Novel Role

Utsugi

Dobashi

Ishizuka

et al. 2006

The Journal of Immunology

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IL-23 is a heterodimeric cytokine composed of a unique p19 subunit and of a p40 subunit that is also common to IL-12. We defined the distinct signaling mechanisms that regulate the LPS-mediated induction of IL-23 p19 and p40 in human macrophages and dendritic cells. We found that the overexpression of dominant-negative Rac1 (N17Rac1) enhanced LPS-induced IL-23 p19 expression but did not alter p40 expression or IL-12 p70 production in PMA-treated THP-1 macrophages and in human monocyte-derived dendritic cells. Although the inhibition of either p38 MAPK or JNK enhanced LPS-induced p19 expression, N17Rac1 did not influence either p38 MAPK or JNK activation. By contrast, N17Rac1 augmented both NF-κB gene expression and p65 trans activation stimulated by LPS without affecting the degradation of IκB-α or DNA binding to NF-κB. Furthermore, small interference RNA of NF-κB p65 attenuated cellular amounts of p65 and suppressed LPS-induced p19 expression but did not affect p40 expression. Our findings indicate that Rac1 negatively controls LPS-induced IL-23 p19 expression through an NF-κB p65 trans activation-dependent, IκB-independent pathway and that NF-κB p65 regulates LPS-induced IL-23 p19, but not p40, expression, which causes differences in the control of IL-23 p19 and p40 expression by Rac1.

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Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression

Cited by 136 publications

References 52 publications

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

Rac1 Negatively Regulates Lipopolysaccharide-Induced IL-23 p19 Expression in Human Macrophages and Dendritic Cells and NF-κB p65 trans Activation Plays a Novel Role

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