Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway

Defects in PTEN a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of t his gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN Those experiments identified 99 candidate ge nes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DU SP1/MKP1, NDRG1/Drg1/ RTP, NFIL3/E4BP4, and a novel gene (PINK], PTEN-induc ed putative kinase). Expression of six of them (PINK], EGR2, HCLS1, DUSP1, BPOZ, and NFIL3) was decreased in ovarian tumors compared with correspondin g normal tissues. Colony-formation assays using plasmid clones designed to express each gene indicated that EGR2 and BPOZ were able to suppress growth of cancer cells significantly; in particular, cancer-cell lines stably exp ressing BPOZ grew more slowly than control cells containing mock vector. Fl ow cytometry suggested that over-expression of BPOZ inhibited progression o f the cell cycle at the G(1)/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was ac celerated. Therefore both genes appear to be novel candidates as mediators of the PTEN growth-suppressive signaling pathway.