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Molecular and Cellular Biology, January 2009, p. 547-558, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.00329-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

USP19 Deubiquitinating Enzyme Supports Cell Proliferation by Stabilizing KPC1, a Ubiquitin Ligase for p27^Kip1

Yu Lu,¹ Olasunkanmi A. J. Adegoke,^1, Alain Nepveu,² Keiichi I. Nakayama,³ Nathalie Bedard,¹ Dongmei Cheng,⁴ Junmin Peng,⁴ and Simon S. Wing^1*

Polypeptide Laboratory, Division of Endocrinology and Metabolism,¹ Molecular Oncology Group, Department of Medicine, McGill University and McGill University Health Centre, Montreal, Quebec, Canada H3A 2B2,² Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan,³ Department of Human Genetics, Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia 30322⁴

Received 26 February 2008/ Returned for modification 5 April 2008/ Accepted 27 October 2008

p27^Kip1 is a cyclin-dependent kinase inhibitor that regulates the G₁/S transition. Increased degradation of p27^Kip1 is associated with cellular transformation. Previous work demonstrated that the ubiquitin ligases KPC1/KPC2 and SCF^Skp2 ubiquitinate p27^Kip1 in G₁ and early S, respectively. The regulation of these ligases remains unclear. We report here that the USP19 deubiquitinating enzyme interacts with and stabilizes KPC1, thereby modulating p27^Kip1 levels and cell proliferation. Cells depleted of USP19 by RNA interference exhibited an inhibition of cell proliferation, progressing more slowly from G₀/G1 to S phase, and accumulated p27^Kip1. This increase in p27^Kip1 was associated with normal levels of Skp2 but reduced levels of KPC1. The overexpression of KPC1 or the use of p27^–/– cells inhibited significantly the growth defect observed upon USP19 depletion. KPC1 was ubiquitinated in vivo and stabilized by proteasome inhibitors and by overexpression of USP19, and it also coimmunoprecipitated with USP19. Our results identify USP19 as the first deubiquitinating enzyme that regulates the stability of a cyclin-dependent kinase inhibitor and demonstrate that progression through G₁ to S phase is, like the metaphase-anaphase transition, controlled in a hierarchical, multilayered fashion.

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* Corresponding author. Mailing address: Polypeptide Laboratory, McGill University, Strathcona Anatomy and Dentistry Building, 3640 University Street, Room W315, Montreal, Quebec, Canada H3A 2B2. Phone: (514) 398-4101. Fax: (514) 398-3923. E-mail: simon.wing{at}mcgill.ca

Published ahead of print on 17 November 2008.

Present address: School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada M3J 1P3.

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Molecular and Cellular Biology, January 2009, p. 547-558, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.00329-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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