Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155.
ABSTRACT The myelodysplastic syndromes (MDSs) comprise a group of disorders characterized by multistage progression from cytopenias to acute myeloid leukemia (AML). They display exaggerated apoptosis in early stages, but lose this behavior during evolution to AML. The molecular basis for loss of apoptosis is unknown. To investigate this critical event, we analyzed phosphatidylinositol (PI) 3'kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3'kinase activates Akt through its production of 3' phosphoinositides. In turn, the phosphoinositides are dephosphorylated by two lipid phosphatases, PTEN and SHIP-1, in myeloid cells. We studied primary MDS-enriched bone marrow cells and bone marrow sections by western blotting, immunohistochemistry, immunocytochemistry and quantitative PCR for components of the SHIP/PTEN/PI 3'kinase signaling circuit. We reported constitutively activated Akt, variable levels of PTEN and uniformly decreased SHIP-1 expression in MDS progenitor cells. Overexpression of SHIP-1, but not the phosphatase-deficient form, inhibited myeloid leukemic growth. Levels of microRNA (miR)-210 and miR-155 transcripts, which target SHIP-1, were increased in CD34(+) MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3' untranslated region of SHIP-1 was confirmed by luciferase reporter assay. Transfection of a myeloid cell line with miR-210 resulted in loss of SHIP-1 protein expression. These data suggest that miR-155 and miR-210/SHIP-1/Akt pathways could serve as clinical biomarkers for disease progression, and that miR-155 and miR-210 might serve as novel therapeutic targets in MDS.
- SourceAvailable from: Daniel Vaiman
Article: Trophoblasts, invasion, and microRNA[Show abstract] [Hide abstract]
ABSTRACT: MicroRNAs (miRNAs) have recently become essential actors in various fields of physiology and medicine, especially as easily accessible circulating biomarkers, or as modulators of cell differentiation. To this respect, terminal differentiation of trophoblasts (the characteristic cells of the placenta in Therian mammals) into syncytiotrophoblast, villous trophoblast, or extravillous trophoblast constitutes a good example of such a choice, where miRNAs have recently been shown to play an important role. The aim of this review is to provide a snapshot of what is known today in placentation mechanisms that are mediated by miRNA, under the angles of materno-fetal immune dialog regulation, trophoblast differentiation, and angiogenesis at the materno-fetal interface. Also, two aspects of regulation of these issues will be highlighted: the part played by oxygen concentration and the specific function of imprinted genes in the developing placenta.Frontiers in Genetics 11/2013; 4:248. DOI:10.3389/fgene.2013.00248
- [Show abstract] [Hide abstract]
ABSTRACT: The predominant expression of the γ and δ isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some success in developing PI3Kδ inhibitors, progress in developing selective inhibitors of PI3Kγ has been rather disappointing. This has prompted the search for alternative targets with which to modulate PI3K signaling specifically in the immune system. One such target is the SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1) which de-phosphorylates PI(3,4,5)P(3) at the D5 position of the inositol ring to create PI(3,4)P(2). In this article, we first describe the current state of PI3K isoform-selective inhibitor development. We then focus on the structure of SHIP-1 and its function in the immune system. Finally, we consider the current state of development of small molecule compounds that potently and selectively modulate SHIP activity and which offer novel opportunities to manipulate PI3K mediated signaling in the immune system.Frontiers in Immunology 01/2012; 3:226. DOI:10.3389/fimmu.2012.00226
- [Show abstract] [Hide abstract]
ABSTRACT: PI3K is critical for the normal function of the immune system, however dysregulated PI3K mediated signaling has been linked to the development of many immune mediated pathologies. This review describes current progress in the development of isoform-specific PI3K inhibitors that hold promise for the treatment of hematopoietic malignancies as well as for inflammatory and autoimmune diseases. A SH2-domain containing inositol-5-phosphatase (SHIP) is a regulator of PI3K signaling, and is also discussed as a potential drug target for immunomodulation and the treatment of leukemia. Recent progress has been made in the development of small molecule compounds that potently and selectively modulate SHIP activity and hence provide a novel mechanism to alter PI3K mediated signaling.Current Opinion in Pharmacology 04/2012; 12(4):444-51. DOI:10.1016/j.coph.2012.02.015 · 4.23 Impact Factor