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

Oncogene volume 19, pages 3684–3692 (2000)Cite this article

Abstract

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 effects 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 effects of Pim-1 on PCD, a hematopoietic cell model was developed in which proliferation was supported efficiently 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 c-Kit, 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 efficiently inhibit PCD as induced by either Co60 or adriamycin, and the dose-dependent nature of this effect was established in several independent clones. By comparison, effects of exogenous Pim-1 on mitogenesis were nominal. In addition, in cell fractionation studies an estimated 25% of Mr 34 000 Pim-1 (but not Mr 44 000 Pim-1) was present in nuclear extracts. Thus, Pim-1 efficiently buffers hematopoietic progenitor cells against death as induced by several clinically important apoptotic agents, and may directly target nuclear effectors.

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Abbreviations

PCD:

programmed cell death

S/T:

serine/threonine

SCF:

stem cell factor

EPO:

erythropoietin

IL:

interleukin

GM-CSF:

granulocyte macrophage colony stimulating factor

Tpo:

thrombopoietin

M r :

molecular weight (relative mass)

ER:

erythropoietin receptor

TUNEL:

TdT-mediated X-dUTP nick end labeling

[3H]dT:

[methyl-3H]thymidine

RTK:

receptor tyrosine kinase

PCNA:

proliferating cell nuclear antigen

ATM:

ataxia-telangiectasia mutated

PARP:

poly (ADP ribose) polymerase

JNK:

c-jun N-terminal kinase

PKC:

protein kinase C

ROS:

reactive oxygen species

PKC:

protein kinase C

PCR:

polymerase chain reaction

FBS:

fetal bovine serum

PBS:

phosphate buffer saline

PI:

propidium iodide

FITC:

fluorescein isothiocyanate

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Acknowledgements

For their generous provision of the following resources, the authors thank Drs Jos Domen and Anton Berns (murine pim-1 cDNA), Maurice Bondurant (murine bcl-xL cDNA), and Steven Pelech (antibodies to Pim-1). We also thank Elaine Kunze for advice and assistance in flow cytometry, and Loretta Muchinsky for assistance in manuscript preparation. This work was supported by grants (to DM Wojchowski) from NIH (HLR0144491) and ACS (RPG9600804LBC).

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Author notes

  1. Shuqing Zhao and Justin N Geiger: S Zhao and JN Geiger contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, 16802, PA, USA

    Bhavana Joneja & Don M Wojchowski

  2. Department of Veterinary Science, The Pennsylvania State University, University Park, Pennsylvania, 16802, PA, USA

    Tony J Pircher, Shuqing Zhao, Justin N Geiger & Don M Wojchowski

  3. Program in Immunobiology, The Pennsylvania State University, University Park, Pennsylvania, 16802, PA, USA

    Tony J Pircher, Shuqing Zhao & Don M Wojchowski

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Pircher, T., Zhao, S., Geiger, J. et al. Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death. Oncogene 19, 3684–3692 (2000). https://doi.org/10.1038/sj.onc.1203684

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