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Molecular and Cellular Biology, June 2003, p. 3897-3908, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3897-3908.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

PIM3 Proto-Oncogene Kinase Is a Common Transcriptional Target of Divergent EWS/ETS Oncoproteins

Benjamin Deneen,¹ Scott M. Welford,^1, Thu Ho,² Felicia Hernandez,³ Irwin Kurland,^1,3 and Christopher T. Denny^1,4,5*

Molecular Biology Institute,¹ The David Geffen UCLA School of Medicine, Department of Pediatrics,² Gwynne Hazen Cherry Memorial Laboratories,⁵ Jonsson Comprehensive Cancer Center,⁴ Department of Medicine, Division of Endocrinology, Diabetes and Metabolism Signaling Laboratory, University of California—Los Angeles, Los Angeles, California 90095³

Received 19 November 2002/ Returned for modification 13 January 2003/ Accepted 3 March 2003

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.

Present address: Department of Radiation Oncology, Stanford University, Stanford, CA 94305.

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