USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1

Yu Lu, Olasunkanmi A.J. Adegoke, Alain Nepveu, Keiichi I. Nakayama, Nathalie Bedard, Dongmei Cheng, Junmin Peng, Simon S. Wing

Research output: Contribution to journalArticle

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Abstract

p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the G1 transition. Increased degradation of p27Kip1 is associated with cellular transformation. Previous work demonstrated that the ubiquitin ligases KPC1/KPC2 and SCFSkp2 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 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.

Original languageEnglish
Pages (from-to)547-558
Number of pages12
JournalMolecular and cellular biology
Volume29
Issue number2
DOIs
Publication statusPublished - Jan 1 2009
Externally publishedYes

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Cyclin-Dependent Kinases
Ligases
Ubiquitin
S Phase
Cell Proliferation
Enzyme Stability
Anaphase
Proteasome Inhibitors
Metaphase
RNA Interference
Growth
Deubiquitinating Enzymes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1. / Lu, Yu; Adegoke, Olasunkanmi A.J.; Nepveu, Alain; Nakayama, Keiichi I.; Bedard, Nathalie; Cheng, Dongmei; Peng, Junmin; Wing, Simon S.

In: Molecular and cellular biology, Vol. 29, No. 2, 01.01.2009, p. 547-558.

Research output: Contribution to journalArticle

Lu, Yu ; Adegoke, Olasunkanmi A.J. ; Nepveu, Alain ; Nakayama, Keiichi I. ; Bedard, Nathalie ; Cheng, Dongmei ; Peng, Junmin ; Wing, Simon S. / USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1. In: Molecular and cellular biology. 2009 ; Vol. 29, No. 2. pp. 547-558.
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