Proteasome-dependent degradation of p27/kip1 in gliomas.
p27/kip1 regulates the G1-S transition of the cell cycle by inhibiting cyclin D-CDK4, cyclin E-CDK2, and cyclin A-CDK2. Modulation of p27 cellular abundance occurs mainly at post-translational level by the ubiquitin-proteasome proteolysis. Although rearrangements and mutations of p27/kip1 are extremely rare events, p27 levels are reduced and associated with a poor prognosis in many human carcinomas. In astrocytic tumors, p27 decreases with advancing anaplasia and is almost absent in glioblastomas. To verify whether the degradation of p27 protein was responsible for its reduced levels in malignant gliomas, p27 degradation activity was tested in 22 tissue extracts that represented high, low, and absent p27 protein levels. p27 protein expression was detected by immunohistochemistry and immunoblot analysis and comparable results between the 2 methods were obtained. Low or undetectable p27 degradation 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. Enhanced degradation activity resulted in malignant gliomas with low or absent p27 protein levels. The proteasome inhibitor LLnL abolished p27 degradation, demonstrating that it occurs in a proteasome-dependent manner. These data suggest that proteasome degradation of p27 may be instrumental in the deregulation of the cell cycle and to the malignant transformation of gliomas.
Department of Neuroscience, University of Turin, Italy.
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R
Piva
I
I
Cancelli
P
P
Cavalla
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S
Bortolotto
J
J
Dominguez
G F
GF
Draetta
D
D
Schiffer
D001254:Astrocytoma / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008840:Microfilament Proteins / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D009124:Muscle Proteins; D009837:Oligodendroglioma / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex
D008840:Microfilament Proteins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex