The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor

Fox, Casey J.; Hammerman, Peter S.; Cinalli, Ryan M.; Master, Stephen R.; Chodosh, Lewis A.; Thompson, Craig B.

doi:10.1101/gad.1105003

Cited by 302 publications

(384 citation statements)

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“…Our finding that rapamycin-generated Th2 cells manifest a broad apoptosis-resistant phenotype may not have been predicted from the numerous studies that associate mTOR inhibition with increased T cell apoptosis (49 -53), but is consistent with knowledge that rapamycin-resistant human CD8 ϩ T cells have an increase of antiapoptotic Bcl-x L (24) and that rapamycin resistance in murine T cells is mediated through the Pim-1 and Pim-2 kinases that confer antiapoptotic, growth, and proliferative effects (44,45). The Th2.R cells used in our study were rapamycin resistant, as they expanded in high-dose rapamycin in the setting of reduced phosphorylation of molecules dependent upon mTOR kinase activity, 4EBP1 and S6 ribosomal protein.…”

Section: Discussionmentioning

confidence: 50%

“…6d). A second potential mechanism for Th2 cell rapamycin resistance may relate to up-regulation of Pim-1 and Pim-2 kinases that confer T cell resistance to rapamycin (44,45). Relative to control Th2 cells, we found that Th2.R cells expressed similar levels of Pim-1 (six of six cases) and Pim-2 (six of six cases).…”

Section: Th2 Cell Rapamycin Resistance: Evaluation Of Potential Mechamentioning

confidence: 55%

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Ex Vivo Rapamycin Generates Apoptosis-Resistant Donor Th2 Cells That Persist In Vivo and Prevent Hemopoietic Stem Cell Graft Rejection

Mariotti

Foley

Jung

et al. 2008

The Journal of Immunology

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Because ex vivo rapamycin generates murine Th2 cells that prevent Graft-versus-host disease more potently than control Th2 cells, we hypothesized that rapamycin would generate Th2/Tc2 cells (Th2/Tc2.R cells) that abrogate fully MHC-disparate hemopoietic stem cell rejection more effectively than control Th2/Tc2 cells. In a B6-into-BALB/c graft rejection model, donor Th2/Tc2.R cells were indeed enriched in their capacity to prevent rejection; importantly, highly purified CD4+ Th2.R cells were also highly efficacious for preventing rejection. Rapamycin-generated Th2/Tc2 cells were less likely to die after adoptive transfer, accumulated in vivo at advanced proliferative cycles, and were present in 10-fold higher numbers than control Th2/Tc2 cells. Th2.R cells had a multifaceted, apoptosis-resistant phenotype, including: 1) reduced apoptosis after staurosporine addition, serum starvation, or CD3/CD28 costimulation; 2) reduced activation of caspases 3 and 9; and 3) increased anti-apoptotic Bcl-xL expression and reduced proapoptotic Bim and Bid expression. Using host-versus-graft reactivity as an immune correlate of graft rejection, we found that the in vivo efficacy of Th2/Tc2.R cells 1) did not require Th2/Tc2.R cell expression of IL-4, IL-10, perforin, or Fas ligand; 2) could not be reversed by IL-2, IL-7, or IL-15 posttransplant therapy; and 3) was intact after therapy with Th2.R cells relatively devoid of Foxp3 expression. We conclude that ex vivo rapamycin generates Th2 cells that are resistant to apoptosis, persist in vivo, and effectively prevent rejection by a mechanism that may be distinct from previously described graft-facilitating T cells.

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Section: Discussionmentioning

confidence: 50%

Section: Th2 Cell Rapamycin Resistance: Evaluation Of Potential Mechamentioning

confidence: 55%

Ex Vivo Rapamycin Generates Apoptosis-Resistant Donor Th2 Cells That Persist In Vivo and Prevent Hemopoietic Stem Cell Graft Rejection

Mariotti

Foley

Jung

et al. 2008

The Journal of Immunology

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“…We further examined the effects of the Pim inhibitor on phosphorylation of 4E-BP1 and expression of growth and survival mediators, because the Pim pathway has been demonstrated to be responsible for the phosphorylation of 4E-BP1 to trigger protein translation for cell growth and survival. 11,18 Treatment with the Pim inhibitor markedly suppressed the phosphorylation of 4E-BP1 along with the reduction of Mcl-1 and c-Myc protein levels in INA-6 and RPMI8226 cells (Figure 4f). However, phosphorylation of Bad and the levels of other apoptosis-related factors including Bcl-xL, Bcl-2 and Bim showed no appreciable change in RPMI8226 cells upon treatment with the Pim inhibitor (Supplementary Figure 4b).…”

Section: Il-6 and Tnf Family Cytokines Cooperatively Enhance Pim-2 Exmentioning

confidence: 97%

The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

et al. 2011

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Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFa, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-jB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.

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“…Both Pim-1 and -2 proteins levels are elevated transcriptionally by the application of interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor, IL-7, and other cytokines to cells (Wang et al, 2001). Mitogen stimulation can regulate the stability of Pim mRNA (Fox et al, 2003). Once increased, Pim protein kinases have a relatively short half-life (about 10 min).…”

Section: Introductionmentioning

confidence: 99%

Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A

Arnold

Lilly

et al. 2007

Oncogene

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The Pim protein kinases are serine threonine protein kinases that regulate important cellular signaling pathway molecules, and enhance the ability of c-Myc to induce lymphomas. We demonstrate that a cascade of events controls the cellular levels of Pim. We find that overexpression of the protein phosphatase (PP) 2A catalytic subunit decreases the activity and protein levels of Pim-1. This effect is reversed by the application of okadaic acid, an inhibitor of PP2A, and is blocked by SV40 small T antigen that is known to disrupt B subunit binding to PP2A A and C subunits. Pim-1 can coimmunoprecipitate with the PP2A regulatory B subunit, B56b, but not B56a, c, d, e or B55a. Using short hairpin RNA targeted at B56b, we demonstrate that decreasing the level of B56b increases the half-life of Pim-1 from 0.7 to 2.8 h, and decreases the ubiquitinylation level of Pim-1. We also find that Pin1, a prolyl-isomerase, is capable of binding Pim-1 and leads to a decrease in the protein level of Pim-1. On the basis of these observations, we hypothesize that phosphorylated Pim-1 binds Pin1 allowing the interaction of PP2A through B56b. Dephosphorylation of Pim-1 then allows for ubiquitinylation and protein degradation of Pim-1.

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The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor

Cited by 302 publications

References 50 publications

Ex Vivo Rapamycin Generates Apoptosis-Resistant Donor Th2 Cells That Persist In Vivo and Prevent Hemopoietic Stem Cell Graft Rejection

Ex Vivo Rapamycin Generates Apoptosis-Resistant Donor Th2 Cells That Persist In Vivo and Prevent Hemopoietic Stem Cell Graft Rejection

The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A

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