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Regulation of p27 Degradation and S-Phase Progression by Ro52 RING Finger Protein

Abdelmajid Sabile ,^1,, Andrea Michael Meyer,^1,4, Christiane Wirbelauer,² Daniel Hess,² Ulrike Kogel,³ Martin Scheffner,³ and Wilhelm Krek^1*

Institute of Cell Biology, ETH-Hönggerberg, 8093 Zurich, Switzerland,¹ Friedrich Miescher Institute, Maulbeerstrasse 66, 4058 Basel, Switzerland,² Department of Biology, University of Konstanz, D-78457 Konstanz, Germany,³ Zurich PhD Program in Molecular Life Sciences, Zurich, Switzerland⁴

Received 23 August 2005/ Returned for modification 22 September 2005/ Accepted 5 June 2006

Ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27 provides a powerful route for enforcing normal progression through the mammalian cell cycle. According to a current model, the ubiquitination of p27 during S-phase progression is mediated by SCF^Skp2 E3 ligase that captures Thr187-phosphorylated p27 by means of the F-box protein Skp2, which in turn couples the bound substrate via Skp1 to a catalytic core complex composed of Cul1 and the Rbx/Roc RING finger protein. Here we identify Skp2 as a component of an Skp1-cullin-F-box complex that is based on a Cul1-Ro52 RING finger B-box coiled-coil motif family protein catalytic core. Ro52-containing complexes display E3 ligase activity and promote the ubiquitination of Thr187-phosphorylated p27 in a RING-dependent manner in vitro. The knockdown of Ro52 expression in human cells with small interfering RNAs causes the accumulation of p27 and the failure of cells to enter S phase. Importantly, these effects are abrogated by the simultaneous removal of p27. Taken together, these data suggest a key role for Ro52 RING finger protein in the regulation of p27 degradation and S-phase progression in mammalian cells and provide evidence for the existence of a Cul1-based catalytic core that utilizes Ro52 RING protein to promote ubiquitination.

These authors contributed equally to this work.

Present address: Forschung Orthopaedie, Uniklinik Balgrist, Forchstrasse 340, 8008 Zurich, Switzerland.

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