PIM3 proto-oncogene kinase is a common transcriptional target of divergent EWS/ETS oncoproteins.
Despite significant structural diversity, present evidence suggests that EWS/ETS fusion proteins promote oncogenesis by transcriptionally modulating a common set of target genes. In order to identify these genes, microarray expression analyses were performed on NIH 3T3 polyclonal populations expressing one of three EWS/ETS fusion genes. The majority of these genes can be grouped into seven functional categories, including cellular metabolism and signal transduction. The biologic significance of these target genes was pursued. The effects of modulating genes involved in metabolism were assessed by flux studies and demonstrated shifts in glucose utilization and lactate production as a result of EWS/FLI1 expression. The proto-oncogene coding for serine/threonine kinase PIM3 was found to one of several genes encoding signal transduction proteins that were up-regulated by EWS/ETS fusions. PIM3 was found to be expressed in a panel of human Ewing's family tumor cell lines. Forced expression of PIM3 promoted anchorage-independent growth. Coexpression of a kinase-deficient PIM3 mutant attenuated EWS/FLI1-mediated NIH 3T3 tumorigenesis in immunodeficent mice.
Molecular Biology Institute, University of California-Los Angeles, Los Angeles, California 90095, USA.
Benjamin
B
Deneen
Scott M
SM
Welford
Thu
T
Ho
Felicia
F
Hernandez
Irwin
I
Kurland
Christopher T
CT
Denny
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D017690:Cell Transplantation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D034802:RNA-Binding Protein EWS / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D034802:RNA-Binding Protein EWS; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases