FUNCTIONAL ANALYSIS OF SKP2 REGARDING P21 REGULATION IN THE DEVELOPING NERVOUS SYSTEM OF THE MOUSE: SKP2 ELIMINATION PROMOTES MDM2/MDM4-MEDIATED PROTEASOMAL DEGRADATION OF P21

The cell cycle inhibitor p21 often is associated with resistance to apoptotic stimuli. Therefore, to improve tumor treatment, it is crucial to understand how p21 is regulated. Post-translationally p21 is degraded by the proteasome. While in in vitro systems the ubiquitin ligase subunit Skp2 has been demonstrated to regulate ubiquitin-dependent degradation of p21 [Bornstein et al., 2003], Mdm2 and Mdm4 have been shown to promote the ubiquitin-independent degradation of p21 [Jin et al., 2003 and 2008]. To understand which one of the two mechanisms is used for p21 degradation in vivo, a functional analysis was carried out using Skp2 knockout mice. While in the 5 day old mouse cerebellum of wild-types p21 can readily be detected after irradiation, in Skp2 knockouts p21 levels were reduced. However, when the Mdm2/Mdm4 inhibitor nutlin-3 was applied to irradiated Skp2 knockouts, p21 levels were restored to levels similar to nutlin-3 treated wild-types. These results are consistent with the view that in both wild-type and knockout animals p21 is degraded by Mdm2/Mdm4 in vivo.