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See detailDifferential signalling through ALK-1 and ALK-5 regulates leptin expression in Mesenchymal Stem Cells
Zeddou, M.; RELIC, Biserka ULg; MALAISE, Olivier ULg et al

in Stem Cells & Development (2012), 21(11), 1948-54

Leptin plays a central role in maintaining energy balance, with multiple other systemic effects. Despite leptin importance in peripheral regulation of mesenchymal stem cells (MSC) differentiation, little ... [more ▼]

Leptin plays a central role in maintaining energy balance, with multiple other systemic effects. Despite leptin importance in peripheral regulation of mesenchymal stem cells (MSC) differentiation, little is known on its expression mechanism. Leptin is often described as adipokine, while it is expressed by other cell types. We have recently shown an in vitro leptin expression, enhanced by glucocorticoids in synovial fibroblasts. Here, we investigated leptin expression in MSC from bone marrow (BM-MSC), cord matrix (UMSC), and primary and dedifferentiated chondrocytes (DCH). Results showed that BM-MSC, but not UMSC, expressed leptin that was strongly enhanced by glucocorticoids. Interestingly, chondrocytes gained leptin expression progressively with dedifferentiation. This dedifferentiation was correlated with downregulation of ALK-5 expression, Smad2 phosphorylation (p-Smad2), and gain of ALK-1 expression and Smad1/5 phosphorylation (p-Smad1/5). TGF-β1 was shown to signal via ALK-5-Smad2/3 and/or ALK-1-Smad1/5 pathways. In BM-MSC, TGF-β1 increased p-Smad2 expression and markedly inhibited endogenous- and glucocorticoidinduced leptin expression, while ALK-5 inhibitor (SB431542) induced and restored this expression. In addition, both prednisolone and <br />SB431542 increased p-Smad1/5 expression. These results suggested ALK-5-Smad2 pathway as inhibitor of leptin expression, while ALK-1-Smad1/5 as activator. Indeed, Smad1 expression silencing induced leptin expression inhibition. Furthermore, prednisolone enhanced the expression of TGF-βRII while decreasing p-Smad2 in BM-MSC and SVF but not in UMSC. In vitro differentiation revealed differential osteogenic potential in SVF, BM-MSC and UMSC that correlates to their leptin expression potential. Our results suggest that ALK-1/ALK-5 balance regulates leptin expression in MSC. It also underlines UMSC as leptin non-producer MSC for cell therapy protocols where leptin expression is not suitable. [less ▲]

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See detailSHIP-1 inhibits CD95/APO-1/Fas-induced apoptosis in primary T lymphocytes and T leukemic cells by promoting CD95 glycosylation independently of its phosphatase activity
Charlier, Edith ULg; Condé, Claude ULg; Zhang, Jing et al

in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2010)

SHIP-1 functions as a negative regulator of immune responses by hydrolyzing phosphatidylinositol-3,4,5-triphosphate generated by PI 3-kinase activity. As a result, SHIP-1 deficiency in mice results in ... [more ▼]

SHIP-1 functions as a negative regulator of immune responses by hydrolyzing phosphatidylinositol-3,4,5-triphosphate generated by PI 3-kinase activity. As a result, SHIP-1 deficiency in mice results in myeloproliferation and B cell lymphoma. On the other hand, SHIP-1 deficient mice have a reduced T cell population, but the underlying mechanisms are unknown. In this work, we hypothesized that SHIP-1 plays anti-apoptotic functions in T cells upon stimulation of the death receptor CD95/APO-1/Fas. Using primary T cells from SHIP-1-/- mice and T leukemic cell lines, we report here that SHIP-1 is a potent inhibitor of CD95-induced death. We observed that a small fraction of the SHIP-1 pool is localized to the endoplasmic reticulum where it promotes CD95 glycosylation. This post-translational modification requires an intact SH2 domain of SHIP-1, but is independent of its phosphatase activity. The glycosylated CD95 fails to oligomerize upon stimulation, resulting in impaired DISC formation and downstream apoptotic cascade. These results uncover an unanticipated inhibitory function for SHIP-1 and emphasize the role of glycosylation in the regulation of CD95 signaling in T cells. This work may also provide a new basis for therapeutic strategies using compounds inducing apoptosis through the CD95 pathway on SHIP-1 negative leukemic T cells. [less ▲]

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See detailRegulation of CD95/APO-1/Fas-induced apoptosis by protein phosphatases.
Gloire, Geoffrey ULg; Charlier, Edith ULg; Piette, Jacques ULg

in Biochemical Pharmacology (2008)

Triggering the CD95/APO-1/Fas receptor by CD95-L induces the assembly of the death-inducing signaling complex (DISC), which permits initiator caspases activation and progression of a signaling cascade ... [more ▼]

Triggering the CD95/APO-1/Fas receptor by CD95-L induces the assembly of the death-inducing signaling complex (DISC), which permits initiator caspases activation and progression of a signaling cascade that culminates in cellular apoptosis. Despite the CD95 receptor does not exhibit any kinase activity by itself, phosphorylation/dephosphorylation events seem important to regulate many aspects of CD95-mediated apoptosis. Here, we try to highlight particularly the importance of protein phosphatases in the modulation of the CD95 system. [less ▲]

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