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.
|Titolo:||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|
|Data di pubblicazione:||17-gen-2011|
|Parole Chiave:||p21 ; Skp2 ; Mdm2 ; Mdm4 ; apoptosis ; irradiation ; in vivo ; proteasome|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Citazione:||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 ; relatore: Lucia Vicentini ; correlatore: Karl-Heinz Herzog. - Milano : Università degli studi di Milano. Universita' degli Studi di Milano, 2011 Jan 17. ((23. ciclo, Anno Accademico 2010.|
|Digital Object Identifier (DOI):||10.13130/pozzi-marco_phd2011-01-17|
|Appare nelle tipologie:||Tesi di dottorato|