Negative regulation of G(1)/S transition by the candidate bladder tumour suppressor gene DBCCR1

Deletion of all or part of chromosome 9q is the most common genetic alterat ion in all stages and grades of bladder cancer. DBCCR1 (deleted in bladder cancer chromosome region candidate I) maps to the chromosome region 9q32-33 , a candidate tumour suppressor locus for bladder cancer, Although no mutat ions of DBCCR1 have been detected in bladder tumours, expression of DBCCR1 is silenced by promoter hypermethylation in 50% of bladder cancer cell line s analysed. Here we sought to provide functional evidence to authenticate D BCCR1 as a tumour suppressor using gene-transfer methods. Exogenous express ion of DBCCR1 protein or an HA epitope-tagged fusion protein, HA-DBCCR1 in NIH3T3 cells and human bladder tumour cell lines resulted in suppression of proliferation. Cell cycle analyses in NIH3T3 cells revealed that DBCCR1-me diated growth inhibition,vas due to an increase in the number of cells in t he G(1) phase of the cell cycle, The levels of apoptosis were not altered. These results demonstrate a role for DBCCR1 in cell cycle control, thereby supporting the hypothesis that this is the tumour suppressor gene targeted by 9q32-33 deletion in bladder cancer. Oncogene (2001) 20, 2956-2964.