Analysis of the cyclin-dependent kinase inhibitor p27(Kip1) in muscle invasive bladder cancer

It has been suggested that a deregulated cell cycle control contributes to the development of human malignancies due to the lass of critical antiproli ferative mechanisms. The cell cycle is controlled at two checkpoints, one a t the G1-S and another at the G2-M transition. Several genes including the structurally related p21(WAF/CIP1) gene, the downstream mediator of the p53 tumor suppressor gene, and the p27(Kip1) gene have been identified as indu cers of cell cycle arrest at the G1 checkpoint when substantial DNA damage has occurred to avoid further replication of the altered genome. Recently, a heat stable 27 kDa protein, the transcript of the p27(Kip1) gene, has bee n identified and was suggested to substantially participate in cell cycle c ontrol at the GI checkpoint. Previous investigations have correlated decrea sed expression of the p27(Kip1) protein with an increased biological aggres siveness of breast and small cell lung cancer. However, the moleculargeneti c analysis of a variety of human malignancies including prostate cancer fai led to identify any alteration at the p27(Kip1) gene locus, therefore sugge sting a loss of p27(Kip1) protein expression to result from post-transcript ional/posttranslational events or from so far unknown regulatory mechanisms . So far, bladder cancer specimens have neither been investigated for p27(K ip1) alterations on the DNA level, nor has the result of moleculargenetic a nalysis been correlated with an immunohistochemically detected expression o f the gene product, the p27(Kip1) protein. The present study is the first t o describe p27(Kip1) gene alterations on the DNA level in 3 of 42 muscle in vasive bladder cancer specimens. In contrast, loss of p27(Kip1) protein exp ression was observed in 14 of 42 (33%) tumors. According to the previously reported observation in a variety of human malignancies, in bladder cancer loss of p27(Kip1) protein expression seems to result from post-transcriptio nal or posttranslational events.