Expression of a Pim-1 transgene accelerates lymphoproliferation and inhibits apoptosis in lpr/lpr mice.

Möröy, Tarik; Grzeschiczek, A; Petzold, Sigrid; Hartmann, Klaus-Ulrich

doi:10.1073/pnas.90.22.10734

Cited by 111 publications

(59 citation statements)

References 26 publications

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“…5 Although lymphoproliferative disease is markedly accelerated, these mice do not show an increased tumour incidence on an lpr background. 43 Similar results were obtained with pim-1 transgenic mice 44 and in mice null for p53 and Fas (ER Cameron et al 1999, unpublished results), both of which display accelerated lymphoproliferative disease but no increase in tumour incidence. By contrast, deregulated expression of Bcl-2 in myeloid cells results in a progressive monocytosis and aberrant myeloid differentiation that in the absence of Fas signalling can progress to a condition resembling acute myeloblastic leukaemia.…”

Section: Cell Death and Differentiationsupporting

confidence: 70%

Fas-independent apoptosis in T-cell tumours induced by the CD2-myc transgene

Cameron¹,

Morton²,

Johnston³

et al. 2000

Cell Death Differ

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Depending on the cellular context, the Myc oncoprotein is capable of promoting cell proliferation or death by apoptosis. These observations suggest that apoptosis in response to deregulated gene expression may represent a natural brake to tumour development. The pathways by which Myc induces apoptosis are as yet poorly characterised although recent observations on rat fibroblasts over-expressing Myc have demonstrated a requirement for the Fas pathway. To investigate the role of Fas in Myc-induced lymphomagenesis we backcrossed CD2-myc mice onto an lpr background. Rates of tumour development and phenotypic properties, including levels of apoptosis were indistinguishable from CD2-myc controls. Further, tumour cell lines derived from mice expressing a regulatable form of Myc showed inducible apoptosis at similar rates regardless of their lpr genotype. These results show that activation of c-myc and loss of Fas do not collaborate in T lymphoma development and that Mycinduced apoptosis in T-cells occurs by Fas-independent pathways. Cell Death and Differentiation (2000) 7, 80 ± 88.

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Section: Cell Death and Differentiationsupporting

confidence: 70%

Fas-independent apoptosis in T-cell tumours induced by the CD2-myc transgene

Cameron¹,

Morton²,

Johnston³

et al. 2000

Cell Death Differ

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“…In addition they illustrate the ability of Pim-1 to inhibit apoptosis as activated further by prior exposure to either Co 60 , or adriamycin (see Figure 2), and provide the important novel result that as expressed in proliferating cells, Pim-1 also signi®cantly inhibits PCD due to either ionizing radiation or adriamycin (see Figures 4 ± 6). As mentioned above, ectopic expression of Pim-1 in lymphoid cells in Em-Pim-1 mice also previously has been shown to inhibit apoptosis as induced by dexamethasone (Moroy et al, 1993). However, relatively little is understood concerning mechanisms of dexamethasone-induced death, and this e ect of Pim-1 was observed only in a FAS-dependent lpr/lpr background.…”

Section: Discussionmentioning

confidence: 82%

“…Based on reports that Pim-1 can attenuate PCD as induced in hematopoietic progenitor cells by cytokine withdrawal (Lilly and Kraft, 1997;Lilly et al, 1999) or in B cells by dexamethasone (Moroy et al, 1993), whether Pim-1 might also bu er PCD in growing progenitor cells as induced by Co 60 or adriamycin was investigated. Speci®cally, an approach was developed by which factor dependent FDCW2 cells could be propagated at normal rates in the absence of endogenously expressed Pim-1.…”

Section: Discussionmentioning

confidence: 99%

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Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death

et al. 2000

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The hematopoietic cell S/T kinase Pim-1 was originally discovered as a target of murine leukemia provirus integration, and when expressed at increased levels is predisposing to lymphomagenesis. Recently, Pim-1 has been shown to enhance the activities of p100, c-Myb and cdc25a, and in part this might explain reported e ects on mitogenesis. In the context of cytokine withdrawal, Pim-1 also can attenuate programmed cell death (PCD). Cytokine withdrawal, however, alters signaling pathways and can complicate the dissection of mitogenic vs apoptotic responses. To better study possible e ects of Pim-1 on PCD, a hematopoietic cell model was developed in which proliferation was supported e ciently by SCF plus EPO in the absence of endogenous Pim-1 gene expression. This was provided by factor-dependent FDCW2 cells that express endogenous and functional cKit, and were transfected stably with truncated Epo receptor form mutated at a Y343 STAT5 binding site. In proliferating cells, exogenously expressed Pim-1 was observed to e ciently inhibit PCD as induced by either Co 60 or adriamycin, and the dose-dependent nature of this e ect was established in several independent clones. By comparison, e ects of exogenous Pim-1 on mitogenesis were nominal. In addition, in cell fractionation studies an estimated 25% of M r 34 000 Pim-1 (but not M r 44 000 Pim-1) was present in nuclear extracts. Thus, Pim-1 e ciently bu ers hematopoietic progenitor cells against death as induced by several clinically important apoptotic agents, and may directly target nuclear e ectors. Oncogene (2000) 19, 3684 ± 3692.

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“…Pim proteins have been suggested to play an important role in growth and proliferation, and a stimulatory role for cell cycle progression has been demonstrated for Pim1. 10,13,[23][24][25][26][27] In the present paper, we provide evidence that Pim2 enhances S-phase entry. These results indicate that Pim2 functions as an active kinase in regulating cell cycle progression during G 1 /S-phase transition.…”

Section: Pim2 Overexpression Synergizes With Fl To Stimulate Prolifermentioning

confidence: 83%

Pim2 complements Flt3 wild-type receptor in hematopoietic progenitor cell transformation

et al. 2007

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Pim2 is a serine/threonine kinase expressed at high levels in several malignancies including acute leukemia. Pim2 protein is induced by oncogenic Fms-like tyrosine kinase-3 (Flt3)-internal tandem duplications (ITD), but not by Flt3 wild-type receptor (Flt3-Wt) in response to Flt3 ligand (FL). Here we show that Pim2 can complement Flt3-Wt signaling and induce transformation similar to Flt3-ITD in myeloid cells. Our data demonstrate that Pim2 is necessary but not sufficient for Flt3-ITD-induced transformation of 32D cells and primary bone marrow cells as assessed by colony assays. Pim2-induced clonogenic growth of FL-treated 32D-Flt3-Wt cells. Proliferation of 32D-Flt3-Wt cells was significantly enhanced in FL-treated Pim2-overexpressing cells. This increase was associated with enhanced Sphase cell cycle progression. Pim2-overexpressing cells were resistant to apoptosis induced by growth factor deprivation or treatment with tyrosine kinase inhibitor (PKC412). The Flt3 point mutant D835Y, which is not able to support colony growth of myeloid cells, also induced clonogenic growth in the presence of Pim2. In conclusion, Pim2 is an important target of Flt3-ITD-induced transformation, and overexpression of Pim2 together with Flt3-Wt or D835Y receptor mimics Flt3-ITDmediated transformation. Pim2 complements with Flt3-Wt signaling to induce proliferation by enhancing G 1 /S-phase progression of the cell cycle.

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Expression of a Pim-1 transgene accelerates lymphoproliferation and inhibits apoptosis in lpr/lpr mice.

Cited by 111 publications

References 26 publications

Fas-independent apoptosis in T-cell tumours induced by the CD2-myc transgene

Fas-independent apoptosis in T-cell tumours induced by the CD2-myc transgene

Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death

Pim2 complements Flt3 wild-type receptor in hematopoietic progenitor cell transformation

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