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Gastric Cancers Overexpress DARPP-32 and a Novel Isoform, t-DARPP¹

Departments of Medicine [W. E-R., M. F. S., G. L., A. B., V. S. C., S. M. P.], Microbiology [M. F. S.], and Pathology [C. A. M., H. F. F.], University of Virginia Health System, Charlottesville, Virginia 22908-0708; Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21230 [E. M.]; and Department of Medical Genetics, University of Helsinki and Helsinki University Central Hospital, Helsinki, 00290 Finland [S. K.]

Gastric carcinoma is the second most common cause of cancer-related death worldwide. Recently, we have demonstrated that expressed sequencetag AA552509 was frequently amplified and the most consistently overexpressed target at 17q in gastric cancers. Herein, we report that DARPP-32 (dopamine and cAMP-regulated phosphoprotein of M_r 32,000) is the target gene for overexpression of expressed sequence tag AA552509. In addition, we have identified full-length cDNA of DARPP-32 (GenBank accession number AF464196) with 467 bp of additional untranslated mRNA nucleotides upstream of the previously known translation start site in exon 1. Additionally, we have discovered a novel truncated isoform of DARPP-32 that we named t-DARPP (GenBank accession number AY070271), which is also overexpressed in gastric cancers. Using quantitative real-time reverse transcription-PCR, Western blots, and staining of tumor tissue arrays, the two DARPP mRNA transcripts and proteins were overexpressed in gastric cancer cells and exhibited abundant protein overexpression in neoplastic but not normal gastric epithelial cells. DARPP-32 is the only known protein that acts as a protein phosphatase 1 inhibitor or a protein kinase A inhibitor. The novel truncated isoform, t-DARPP, lacks the phosphorylation site related to protein phosphatase 1 inhibition but maintains the phosphorylation site with the protein kinase A inhibitory effect. Our results reveal for the first time the presence of these signaling molecules in human cancer and suggest that they may be important for gastric tumorigenesis.

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