Abstract A54: CnABP, a novel modulator of the Calcineurin‐NFAT signaling pathway, is overexpressed in Wilms' tumors and promotes cell migration

Wilms9 tumor (WT) is a classical cancer type that arises from abnormal differentiation of kidney progenitor cells, and occurs at a frequency of 1 in 10,000 live births, accounting for approx. 90% of childhood kidney cancer. Abnormally high levels of Pax2 (paired‐box protein 2), a key regulator of kidney development, have been observed in both WT and renal cell carcinoma, which correlate with proliferation and increased invasiveness. Therefore the misexpression of Pax2 and its target genes may play an important role in tumor initiation and/or progression. To test this, we screened for target genes of Pax2 by cDNA microarray in the embryonic kidney. We identified CnABP (Calcineurin A Binding Protein), a novel gene under Pax2 regulation. In situ hybridization indicates that CnABP coexpresses with Pax2 in the condensing mesenchyme, the abnormal differentiation of which gives rise to WT. Furthermore, expression analysis by quantitative PCR indicates that CnABP is overexpressed in more than 70% of Wilms9 tumors. Interestingly, in the proportion of tumors with upregulated PAX2 expression, more than 80% also overexpress CnABP. We characterized CnABP as a membrane‐anchored protein that primarily promotes cell proliferation and migration. Mediators of these activities were investigated by Yeast‐two‐hybrid and immunoprecipitation, which identified an interaction between CnABP and Calcineurin A, the catalytic subunit of a calcium‐responsive serine/threonine phosphatase Calcineurin. We showed that CnABP modulates phosphatase activities of Calcineurin, which consequently inhibits calcium/Calcineurin‐dependent NFAT nuclear translocation. We further demonstrated that the inhibition of NFAT nuclear localization results in reduced NFAT‐specific transcriptional activity. Components of the Calcineurin complex have been reported as differentially expressed genes distinguishing recurrent from non‐recurrent Wilms9 tumors. This is in line with the evidence we presented, as CnABP is upregulated in Wilms9 tumors and is shown to promote proliferation and migration. Citation Information: Cancer Res 2009;69(23 Suppl):A54.