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A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome.

The EMBO journal | May 15, 2001

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 is a key regulator of cell-cycle progression and its expression is tightly regulated at the level of transcription and by proteasome-dependent proteolysis. The turnover of p21WAF1/CIP1 by proteasomes does not always require the ubiquitylation of p21WAF1/CIP1 suggesting that there could be an alternative pathway into the proteasome. Here we show that the C8 alpha-subunit of the 20S proteasome interacts with the C-terminus of p21WAF1/CIP1 and mediates the degradation of p21WAF1/CIP1. A small deletion in this region that disrupts binding to C8 increased the half-life of p21WAF1/CIP1 expressed in vivo. In contrast a deletion that increased the affinity between C8 and p21WAF1/CIP1 significantly reduced the stability of the latter. These data suggest that interaction with a 20S proteasome alpha-subunit is a critical determinant of p21WAF1/CIP1 turn-over and show how non-ubiquitylated molecules might bypass the 19S regulator of the proteasome and become targeted directly to the 20S, core protease. Consistent with this, p21WAF1/CIP1 was degraded rapidly by purified 20S proteasomes in a manner that was dependent on the C8-interaction domain.

Pubmed ID: 11350925 RIS Download

Mesh terms: 3T3 Cells | Amino Acid Sequence | Animals | Binding Sites | Cell Nucleus | Cyclin-Dependent Kinase Inhibitor p21 | Cyclins | Cysteine Endopeptidases | Humans | Mice | Molecular Sequence Data | Multienzyme Complexes | Proliferating Cell Nuclear Antigen | Proteasome Endopeptidase Complex | Protein Folding | Tumor Cells, Cultured