INCREASED PROTEASOME-DEPENDENT DEGRADATION OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P27 IN AGGRESSIVE COLORECTAL CARCINOMAS

The cell-cycle inhibitor p27 is a potential tumor suppressor, but its gene has never been found inactivated in human tumors(1-4). Because ce ll-cycle regulation of p27 cellular abundance occurs at the post-trans criptional level(5-7), we analyzed p27 protein expression and degradat ion in human colorectal carcinomas. Proteasome-mediated degradation ac tivity of p27 was compared with its protein levels in a subset of tumo r samples. We found that carcinomas with low or absent p27 protein dis played enhanced proteolytic activity specific for p27, suggesting that low p27 expression can result from increased proteasome-mediated degr adation rather than altered gene expression. Patients whose tumors exp ressed p27 had a median survival of 151 months, whereas patients who l acked p27 (10%) had a median survival of 69 months. By multivariate an alysis, p27 was found to be an independent prognostic marker. Lack of p27 was associated with poor prognosis (2.9 risk ratio for death; P = 0.003). The absence of p27 protein expression is thus a powerful negat ive prognostic marker in colorectal carcinomas, particularly in stage II tumors, and thereby may help in the selection of patients who will benefit from adjuvant therapy. These data suggest that aggressive tumo rs may result from the selection of a clone or clones that lack p27 du e to increased proteasome-mediated degradation.