Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death.
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 34000 Pim-1 (but not Mr 44000 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.
Pircher
T J
TJ
Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park 16802, USA.
Zhao
S
S
Geiger
J N
JN
Joneja
B
B
Wojchowski
D M
DM
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D009153:Mutagens / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1
D009153:Mutagens; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D003035:Cobalt; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1