Proteasome-dependent degradation of p27/kip1 in gliomas

p27/kip1 regulates the G1-S transition of the cell cycle by inhibiting cycl in D-CDK4, cyclin E-CDK2, and cyclin A-CDK2. Modulation of p27 cellular abu ndance occurs mainly at post-translational level by the ubiquitin-proteasom e proteolysis. Although rearrangements and mutations of p27/kip1 are extrem ely rare events, p27 levels are reduced and associated with a poor prognosi s in many human carcinomas. In astrocytic tumors, p27 decreases with advanc ing anaplasia and is almost absent in glioblastomas. To verify whether the degradation of p27 protein was responsible for its reduced levels in malign ant gliomas, p27 degradation activity was tested in 22 tissue extracts that represented high, low, and absent p27 protein levels. p27 protein expressi on was detected by immunohistochemistry and immunoblot analysis and compara ble results between the 2 methods were obtained. Low or undetectable p27 de gradation activity was found in samples that displayed high levels of p27, i.e. all 4 normal brain biopsies, and 4 out of 6 grade II astrocytomas. Enh anced degradation activity resulted in malignant gliomas with low or absent p27 protein levels. The proteasome inhibitor LLnL abolished p27 degradatio n, demonstrating that it occurs in a proteasome-dependent manner. These dat a suggest that proteasome degradation of p27 may be instrumental in the der egulation of the cell cycle and to the malignant transformation of gliomas.