Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3β signaling and leads to an increased transit time through the G1 phase of the cell cycle

Horn, Stefan; Endl, Elmar; Fehse, Boris; Weck, Markus M.; Mayr, Georg W.; Jücker, Manfred

doi:10.1038/sj.leu.2403529

Cited by 66 publications

(75 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Differential expression of the lipid phosphatase SHIP-1 in CEM and Jurkat cells Previous works have shown that the Jurkat leukemic cell line is deficient in SHIP-1 at the protein level, but that CEM cells express the protein normally (Bruyns et al, 1999;Freeburn et al, 2002;Horn et al, 2004). To confirm that difference in our cell lines, we carried out Western blotting analysis with specific antibodies raised against SHIP-1 and another inositol lipid phosphatase, namely SHIP-2.…”

Section: Resultsmentioning

confidence: 76%

“…Cells lacking SHIP-1 (i.e. Jurkat cells) present a very high basal level of PtdIns(3,4,5)P 3 and a subsequent constitutive Akt activation, which is not the case for SHIP-1-positive cells (Freeburn et al, 2002;Horn et al, 2004). This difference might in turn influence a very large number of cellular events, including IKK activation (Cantley, 2002).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Restoration of SHIP-1 activity in human leukemic cells modifies NF-κB activation pathway and cellular survival upon oxidative stress

et al. 2006

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Restoration of SHIP-1 activity in human leukemic cells modifies NF-κB activation pathway and cellular survival upon oxidative stress

et al. 2006

View full text Add to dashboard Cite

“…For example, cytolethal distending toxin subunit B (CdtB) is an immunotoxin produced by Actinobacillus actinomycetemcomitans that can hydrolyze PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2 (50). Exposure to CdtB leads to cell cycle arrest and death by apoptosis, consistent with the down-regulation of proliferation observed upon overexpression of SHIP in leukemic cell lines (51). Lymphocytes are considerably more sensitive to CdtB than are other cell types.…”

Section: Lipid Phosphatases Are Exploited By Pathogensmentioning

confidence: 71%

Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes

Harris

Parry

Westwick

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The phosphoinositide 3-kinase signaling pathway has been implicated in a range of T lymphocyte cellular functions, particularly growth, proliferation, cytokine secretion, and survival. Dysregulation of phosphoinositide 3-kinase-dependent signaling and function in leukocytes, including B and T lymphocytes, has been implicated in many inflammatory and autoimmune diseases. As befits a pivotal signaling cascade, several mechanisms exist to ensure that the pathway is tightly regulated. This minireview focuses on two lipid phosphatases, viz. the 3 -phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SHIP (Src homology 2 domain-containing inositol-5-phosphatase). We discuss their role in regulating T lymphocyte signaling as well their potential as future therapeutic targets.The PI3K 3 pathway plays a central role in regulating many biological processes, primarily via the generation of the potent second messenger PtdIns(3,4,5)P 3 , which acts as a docking site at the plasma membrane, recruiting and activating proteins containing pleckstrin homology (PH) domains (1). These downstream PI3K effectors include PDK-1 (3Ј-phosphoinositide-dependent kinase-1), which phosphorylates and activates the AGC protein kinases, including protein kinase B/Akt. Other kinases such as Tec family kinases can also interact directly with PtdIns(3,4,5)P 3 , as can GTPase-activating proteins and guanine nucleotide exchange factors as well as scaffolding proteins that nucleate the assembly of key signaling complexes (1, 2). PI3K and T LymphocytesT cells express all three class 1A PI3K isoforms (p110␣, p110␤, and p110␦), which are regulated by protein-tyrosine kinase-coupled receptors, as well as class 1B p110␥, which is activated by G protein-coupled receptors (GPCRs). The T cell antigen receptor (TCR), CD28 family co-stimulatory receptors, and cytokine receptors activate class 1A isoforms (3). Chemokines (by virtue of interacting with GPCRs), activate mainly class 1B PI3K (4). Use of pharmacological tools in leukemic human T cell lines first indicated a possible role for PI3K in T cell activation (5). Mice with a knock-in point mutation of p110␦ that abolishes kinase activity exhibit selective impairments in TCR signaling and reduced proliferation in vitro (6) and impaired function of CD4 ϩ CD25 ϩ Foxp3 ϩ T Reg cells (7). Interestingly, mice lacking both p110␥ and p110␦ show much more profound defects in thymocyte development and survival compared with mice lacking individual isoforms, indicating that these isoforms serve partially redundant functions in thymocytes (8, 9). Pathological consequences of combined p110␥␦ deficiency includes T cell lymphopenia, which leads to multiple-organ inflammation (10). Surprisingly, mice with T cellspecific loss of class 1A PI3K exhibit largely normal thymocyte development, and peripheral T cell numbers and subsets are unimpaired in young animals (11,12). In vitro proliferation of T cells from these mice in response to TCR ligation is abrogated, and there is complete loss of PI3K sig...

show abstract

“…7 A SHIP-1 mutant without enzymatic activity was created by exchanging the aspartic acid at position 672 in the second conserved motif of the inositol phosphatase domain to alanine (D672A). The resulting mutant did not reveal any detectable enzymatic activity in an in vitro inositol 5-phosphatase assay using Ins(1,3,4,5)P 4 as substrate (data not shown).…”

Section: Retroviral Vectors and Generation Of Pseudotyped Viral Partimentioning

confidence: 99%

“…Restoration of SHIP-1 activity in a human SHIP-1-deficient leukemia cell line (Jurkat) resulted in a reduced proliferation owing to an increased transit time through the G1 phase of the cell cycle. 7 Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disease of early childhood characterized by excessive proliferation of the myeloid and monocytic lineage. This abnormal myeloproliferation appears to be the result of a selective hypersensitivity of the myeloid JMML progenitor cells to GM-CSF.…”

Section: Introductionmentioning

confidence: 99%

Gene transfer of SHIP-1 inhibits proliferation of juvenile myelomonocytic leukemia cells carrying KRAS2 or PTPN11 mutations

Metzner

Horstmann²,

Ortmeyer

et al. 2007

Gene Ther

Self Cite

View full text Add to dashboard Cite

Juvenile myelomonocytic leukemia (JMML) is a malignant disease of early childhood characterized by a hypersensitivity to granulocyte/macrophage colony-stimulating factor (GM-CSF). Mutations in RAS or PTPN11 are frequently detected in JMML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP-1) is a negative regulator of GM-CSF signaling, and inactivation of SHIP-1 in mice results in a myeloproliferative disease. Here, we report the effects of SHIP-1 expression on GM-CSF-dependent proliferation and colony formation of human hematopoietic cells. After retroviral-mediated transduction of SHIP-1 into CD34 + cells from cord blood of healthy newborns or peripheral blood of JMML patients carrying mutations in KRAS2 or PTPN11, we observed a reduction in GM-CSF-dependent proliferation and colony formation. An enzymatically inactive form of SHIP-1 (D672A) had no effect. These data indicate that SHIP-1 can effectively block GM-CSF hypersensitivity in JMML progenitor cells with mutations in KRAS2 or PTPN11 and may be a useful approach for the treatment of JMML patients.

show abstract

Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3β signaling and leads to an increased transit time through the G1 phase of the cell cycle

Cited by 66 publications

References 63 publications

Restoration of SHIP-1 activity in human leukemic cells modifies NF-κB activation pathway and cellular survival upon oxidative stress

Restoration of SHIP-1 activity in human leukemic cells modifies NF-κB activation pathway and cellular survival upon oxidative stress

Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes

Gene transfer of SHIP-1 inhibits proliferation of juvenile myelomonocytic leukemia cells carrying KRAS2 or PTPN11 mutations

Contact Info

Product

Resources

About