Gene structure, expression profiling and mutation analysis of the tumour suppressor SHIP1 in Caucasian acute myeloid leukaemia

Gilby, Daniel C; Goodeve, Anne; Winship, Peter R.; Valk, Peter J.M.; Delwel, Ruud; Reilly, John T.

doi:10.1038/sj.leu.2404864

Cited by 30 publications

(23 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetic lesions in MDS are heterogeneous, but none have been reported in chromosome 2q37.1 where the SHIP-1 gene resides. Though found in Chinese patients with AML (Luo et al, 2004), mutations in the coding region of SHIP-1 are rare in Caucasian patients (Gilby et al, 2007). Having confirmed that SHIP-1 protein levels are decreased in these patients, we investigated three major mechanisms by which this effect is known to occur in other malignancies: increased destruction of SHIP-1 by proteasomes, hypermethylation and regulation of transcripts by microRNAs (miRs).…”

Section: Resultsmentioning

confidence: 87%

See 1 more Smart Citation

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

et al. 2012

View full text Add to dashboard Cite

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 0 kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3 0 kinase activates Akt through its production of 3 0 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 0 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 þ MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3 0 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.

show abstract

Section: Resultsmentioning

confidence: 87%

“…Although there has been no report of the role in human cancer (Gilby et al, 2007), ablation of SHIP-1 gene in mice leads to myeloproliferative disease (Helgason et al, 1998;Lakhanpal et al, 2010). SHIP-1 deficiency might explain other characteristics of MDS.…”

Section: Discussionmentioning

confidence: 99%

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

et al. 2012

View full text Add to dashboard Cite

show abstract

“…SHIP1 catalyzes the 5-dephosphorylation of PtdIns(3,4,5)P 3 ( 154,(157)(158)(159)(160) and Ins(1,3,4,5)P 4 ( 154,157,158,161 ) and Ins(1,4,5)P 3 ( 154,157,158 ) were initially reported not to be substrates for SHIP1 in vitro; however, more recent studies have reported that SHIP1 can indeed dephosphorylate PtdIns(4,5)P 2 in vitro ( 159,162 ). Mutations in SHIP1 have only been found infrequently in patients with acute myeloid leukemia ( 163 ).…”

Section: The Sac Phosphatases and Cancermentioning

confidence: 99%

Phosphatidylinositolphosphate phosphatase activities and cancer

Rudge

Wakelam

2016

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org kinase pathways in regulating phosphoinositide signaling; however, all signaling pathways are subject to negative as well as positive control, pointing to a key role for inositol phospholipid phosphatases in cell and tissue regulation in health and disease. This review focuses upon this aspect of regulation, considering the importance of the many phosphatases that can act upon phosphoinositides, and we further consider the importance of each in malignancy. PHOSPHOINOSITIDE 3-KINASESIn mammals, the phosphoinositide 3-kinase (PI3K) isoforms responsible for phosphorylating the 3-hydroxyl group of the inositol headgroup of PtdIns, PtdIns(4)P, and PtdIns(4,5)P 2 have been divided into three classes: class I, class II, and class III.In response to activation of cell surface receptors, class I PI3Ks are responsible for phosphorylating PtdIns(4,5)P 2 to generate PtdIns(3,4,5)P 3 ( 3 ). There are four class I PI3Ks that exist as heterodimers of regulatory and catalytic subunits. The four distinct catalytic subunits, p110 ␣ , -␤ , -␥ , and -␦ , are further divided into class IA (p110 ␣ , -␤ , and -␦ ) and class IB (p110 ␥ ). Class IA PI3Ks bind the SH2 domain containing the p85 family of regulatory subunits (p85 ␣ , p85 ␤ , and p55) that bind to protein tyrosine phosphate residues in activated receptors, thus relieving p85-mediated Abstract Signaling through the phosphoinositide 3-kinase pathways mediates the actions of a plethora of hormones, growth factors, cytokines, and neurotransmitters upon their target cells following receptor occupation. Overactivation of these pathways has been implicated in a number of pathologies, in particular a range of malignancies. The tight regulation of signaling pathways necessitates the involvement of both stimulatory and terminating enzymes; inappropriate activation of a pathway can thus result from activation or inhibition of the two signaling arms . The focus of this review is to discuss, in detail, the activities of the identifi ed families of phosphoinositide phosphatase expressed in humans, and how they regulate the levels of phosphoinositides implicated in promoting malignancy. A series of tightly regulated lipid kinase and phosphatase enzyme activities coordinately convert phosphatidylinositol (PtdIns) into a network of phosphorylated derivatives, collectively called phosphoinositides. These differ in the number and position of the phosphate groups on the inositol head group: three PtdIns monophosphate isomers [PtdIns(3)P, PtdIns(4)P, and PtdIns(5)P], three PtdIns bisphosphate isomers [PtdIns(3,4)P 2 , PtdIns(3,5) P 2 , and PtdIns(4,5)P 2 ], and a single trisphosphate isomer [PtdIns(3,4,5)Phosphoinositide signaling is an extensively studied topic with clear evidence linking the pathway from the kinase to activation of AKT and TOR to a number of disease states. While these include malignancies, there is also strong evidence for other diseases, such as overgrowth syndromes. Most studies have focused upon the importance of the ...

show abstract

“…9 In recent years, mutations in the SHIP1 encoding INPP5D gene have been detected in patients with acute myeloid leukemia (AML) implicating a role of SHIP1 also in the development of AML. [10][11][12] Furthermore, we have demonstrated that overexpression of SHIP1 in primary leukemia cells from patients suffering from juvenile myelomonocytic leukemia or AML reduces the proliferation of the leukemia cells in vitro. 13,14 In addition, it has been shown that accompanying deletion of PTEN and SHIP1 causes development of lethal B cell lymphomas in mice.…”

Section: Introductionmentioning

confidence: 99%

The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies

Ehm

Nalaskowski

Wundenberg

et al. 2015

Nucleus

View full text Add to dashboard Cite

The inositol 5-phosphatase SHIP1 is a negative regulator of signaling processes in haematopoietic cells. By converting PI(3,4,5)P 3 to PtdIns(3,4)P 2 at the plasma membrane, SHIP1 modifies PI3-kinase mediated signaling. We have recently demonstrated that SHIP1 is a nucleo-cytoplasmic shuttling protein and SHIP1 nuclear puncta partially colocalize with FLASH, a component of nuclear bodies. In this study, we demonstrate that endogenous SHIP1 localizes to intranucleolar regions of both normal and leukemic haematopoietic cells. In addition, we report that ectopically expressed SHIP1 accumulates in nucleolar cavities and colocalizes with the tumor suppressor protein p53 and components of PML nuclear bodies (e.g. SP100, SUMO-1 and CK2). Moreover, SHIP1 also colocalizes in nucleolar cavities with components of the ubiquitin-proteasome pathway. By using confocal microscopy data, we generated 3D-models revealing the enormous extent of the SHIP1 aggresomes in the nucleolus. Furthermore, treatment of cells with the proteasome inhibitor MG132 causes an enlargement of nucleolar SHIP1 containing structures. Unexpectedly, this accumulation can be partially prevented by treatment with the inhibitor of nuclear protein export Leptomycin B. In recent years, several proteins aggregating in nucleolar cavities were shown to be key factors of neurodegenerative diseases and cancerogenesis. Our findings support current relevance of nuclear localized SHIP1.

show abstract

Gene structure, expression profiling and mutation analysis of the tumour suppressor SHIP1 in Caucasian acute myeloid leukaemia

Cited by 30 publications

References 7 publications

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

Phosphatidylinositolphosphate phosphatase activities and cancer

The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies

Contact Info

Product

Resources

About