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Fbw7alpha and fbw7gamma collaborate to shuttle cyclin e1 into the nucleolus for multiubiquitylation

Academic Article
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Overview

authors

  • Bhaskaran, N.
  • van Drogen, F.
  • Ng, H. F.
  • Kumar, R.
  • Ekholm-Reed, S.
  • Peter, M.
  • Sangfelt, O.
  • Reed, Steven

publication date

  • January 2013

journal

  • Molecular and Cellular Biology  Journal

abstract

  • Cyclin E1, an activator of cyclin-dependent kinase 2 (Cdk2) that promotes replicative functions, is normally expressed periodically within the mammalian cell cycle, peaking at the G(1)-S-phase transition. This periodicity is achieved by E2F-dependent transcription in late G(1) and early S phases and by ubiquitin-mediated proteolysis. The ubiquitin ligase that targets phosphorylated cyclin E is SCF(Fbw7) (also known as SCF(Cdc4)), a member of the cullin ring ligase (CRL) family. Fbw7, a substrate adaptor subunit, is expressed as three splice-variant isoforms with different subcellular distributions: Fbw7α is nucleoplasmic but excluded from the nucleolus, Fbw7β is cytoplasmic, and Fbw7γ is nucleolar. Degradation of cyclin E in vivo requires SCF complexes containing Fbw7α and Fbw7γ, respectively. In vitro reconstitution showed that the role of SCF(Fbw7α) in cyclin E degradation, rather than ubiquitylation, is to serve as a cofactor of the prolyl cis-trans isomerase Pin1 in the isomerization of a noncanonical proline-proline bond in the cyclin E phosphodegron. This isomerization is required for subsequent binding and ubiquitylation by SCF(Fbw7γ). Here we show that Pin1-mediated isomerization of the cyclin E phosphodegron and subsequent binding to Fbw7γ drive nucleolar localization of cyclin E, where it is ubiquitylated by SCF(Fbw7γ) prior to its degradation by the proteasome. It is possible that this constitutes a mechanism for rapid inactivation of phosphorylated cyclin E by nucleolar sequestration prior to its multiubiquitylation and degradation.

subject areas

  • Animals
  • Cell Cycle Proteins
  • Cell Line
  • Cell Nucleolus
  • Cyclin E
  • F-Box Proteins
  • Fibroblasts
  • HEK293 Cells
  • Humans
  • Mice
  • Nucleoplasmins
  • Oncogene Proteins
  • Peptidylprolyl Isomerase
  • Phosphorylation
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors
  • Protein Isoforms
  • Protein Transport
  • S Phase
  • Ubiquitin-Protein Ligases
  • Ubiquitination
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Identity

PubMed Central ID

  • PMC3536299

International Standard Serial Number (ISSN)

  • 1098-5549 (Electronic) 0270-7306 (Linking)

Digital Object Identifier (DOI)

  • 10.1128/mcb.00288-12

PubMed ID

  • 23109421
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Additional Document Info

start page

  • 85

end page

  • 97

volume

  • 33

issue

  • 1

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