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PRC17, a Novel Oncogene Encoding a Rab GTPase-activating Protein, Is Amplified in Prostate Cancer

Tularik Inc., South San Francisco, California 94080 [L. P., X. B. L., T. H.]; Tularik Inc., Genomics Division, Greenlawn, New York 11740 [Y. P., Y. Y., W. G. v. E., K. C. Q. N., S. P., J. L.]; and Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109 [M. R.]

We used cDNA-based genomic microarrays to examine DNA copy number changes in a panel of prostate tumors and found a previously undescribed amplicon on chromosome 17 containing a novel overexpressed gene that we termed prostate cancer gene 17 (PRC17). When overexpressed in 3T3 mouse fibroblast cells, PRC17 induced growth in low serum, loss of contact inhibition, and tumor formation in nude mice. The PRC17 gene product contains a GTPase-activating protein (GAP) catalytic core motif found in various Rab/Ypt GAPs, including RN-Tre. Similar to RN-Tre, we found that PRC17 protein interacts directly with Rab5 and stimulates its GTP hydrolysis. Point mutations that alter conserved amino acid residues within the PRC17 GAP domain abolished its transforming abilities, suggesting that GAP activity is essential for its oncogenic function. Whereas PRC17 is amplified in 15% of prostate cancers, it is highly overexpressed in approximately one-half of metastatic prostate tumors. The potent oncogenic activity of PRC17 is likely to influence the tumorigenic phenotype of these prostate cancers.

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