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Molecular and Cellular Biology, February 2009, p. 919-928, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00907-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Lysine-Independent Turnover of Cyclin G1 Can Be Stabilized by B'{alpha} Subunits of Protein Phosphatase 2A{triangledown}

Hongyun Li,{dagger} Koji Okamoto,{ddagger} Melissa J. Peart, and Carol Prives*

Department of Biological Sciences, Columbia University, New York, New York 10027

Received 6 June 2008/ Returned for modification 11 July 2008/ Accepted 24 October 2008

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 G1-137) 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 G1-137. Furthermore, the presence of a six-Myc tag at the N terminus of cyclin G1-137 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'{alpha}1 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.

* Corresponding author. Mailing address: Department of Biological Sciences, Columbia University, New York, NY 10027. Phone: (212) 854-2557. Fax: (212) 865-8142. E-mail: clp3{at}columbia.edu

{triangledown} Published ahead of print on 3 November 2008.

{dagger} Present address: Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Rockville, MD 20852.

{ddagger} Present address: National Cancer Center Research Institute, 5-1-1 Tsukiji Bunkyo-ku, Tokyo 1040045, Japan.

Molecular and Cellular Biology, February 2009, p. 919-928, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00907-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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