Open AccessUSP19 Deubiquitinating Enzyme Supports Cell Proliferation by Stabilizing KPC1, a Ubiquitin Ligase for p27Kip1
Author(s) -
Lu Yu,
Olasunkanmi A. J. Adegoke,
Alain Nepveu,
Keiichi I. Nakayama,
Nathalie Bédard,
Dongmei Cheng,
Junmin Peng,
Simon S. Wing
Publication year - 2009
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00329-08
Subject(s) - deubiquitinating enzyme , biology , ubiquitin ligase , ubiquitin , enzyme , cell growth , dna ligase , microbiology and biotechnology , ubiquitin protein ligases , biochemistry , gene
p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the G1 /S transition. Increased degradation of p27Kip1 is associated with cellular transformation. Previous work demonstrated that the ubiquitin ligases KPC1/KPC2 and SCFSkp2 ubiquitinate p27Kip1 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 p27Kip1 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 p27Kip1 . This increase in p27Kip1 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.