Lysine-independent turnover of cyclin G1 can be stabilized by B'alpha subunits of protein phosphatase 2A.
Although the cyclin G1 gene is known to be regulated at the transcriptional level by p53, less is understood about the turnover of its protein product. We found that ectopically and endogenously expressed cyclin G1 protein is highly unstable and is degraded by a proteasome-mediated pathway. The N-terminal 137 amino ... acids of cyclin G1 (cyclin G(1-137)) are necessary and sufficient for both cyclin G1 ubiquitination and turnover. Interestingly, a mutant cyclin G1 (8KR) in which all lysine residues in this region have been replaced with arginine can be both ubiquitinated in cells and stabilized by a proteasome inhibitor to a similar extent as wild-type cyclin G(1-137). Furthermore, the presence of a six-Myc tag at the N terminus of cyclin G(1-137) significantly inhibits the protein's turnover, suggesting a role for the extreme N terminus of the protein in ubiquitin-mediated proteolysis. Although we and others previously showed that cyclin G1 protein can bind to MDM2, which functions as an E3 ubiquitin ligase to p53 and itself, cyclin G1 protein can be degraded in cells without MDM2 and p53. Interestingly, the B'alpha1 subunit of the serine/threonine protein phosphatase 2A, which binds to cyclin G1, can stabilize cyclin G1 under unstressed conditions and upon DNA damage, as well as inhibit the ability of cyclin G1 to be ubiquitinated. Our results thus indicate that proteasomal turnover of cyclin G1 is regulated by noncanonical processes.
Mesh Terms:
Animals, Cyclin G, Cyclin G1, Cyclins, DNA Damage, Enzyme Inhibitors, Epitopes, Hela Cells, Humans, Lysine, Mice, NIH 3T3 Cells, Proteasome Endopeptidase Complex, Protein Phosphatase 2, Protein Processing, Post-Translational, Protein Stability, Protein Subunits, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Ubiquitination
Animals, Cyclin G, Cyclin G1, Cyclins, DNA Damage, Enzyme Inhibitors, Epitopes, Hela Cells, Humans, Lysine, Mice, NIH 3T3 Cells, Proteasome Endopeptidase Complex, Protein Phosphatase 2, Protein Processing, Post-Translational, Protein Stability, Protein Subunits, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Ubiquitination
Mol. Cell. Biol.
Date: Feb. 01, 2009
PubMed ID: 18981217
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