IndraLab

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USP48 activates MDM2. 9 / 9
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"Moreover, these results also suggested that USP48 does not mediate Mdm2 stabilization through the deubiquitination of other Mdm2 regulators."
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"Recently, USP48 has also been shown to promote the stability of Mdm2 that in turn results in enhanced degradation of p53 42, which has been associated to FA cell death 43."
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"To determine whether the observed USP48 mediated Mdm2 upregulation might reflect increased stability on the protein level, we performed a cycloheximide (CHX) chase assay in U2OS cells transfected either with the Mdm2 construct alone or in combination with USP48."
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"Interestingly, when we analyzed the pattern of Mdm2 ubiquitination in the presence of the deubiquitinase defective mutant USP48 C98S, we again observed that less ubiquitin was attached to Mdm2 via lysine 48 compared to other lysines, suggesting that the deubiquitinase activity of USP48 was not responsible for the previously observed difference and supporting our notion that USP48 did not target Mdm2 with its deubiquitinase activity."
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"We were surprised to find that USP48 caused Mdm2 stabilization that was not accompanied by a significant decrease in the overall levels of Mdm2 ubiquitination, which was unexpected (XREF_FIG)."
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"Nevertheless, we can not exclude the possibility that USP48 (and its deubiquitinase inactive mutants) are capable of recruiting another deubiquitinase responsible for trimming K48 linked ubiquitin, and future studies are necessary to determine the exact mechanism by which USP48 promotes Mdm2 stability."
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"As Mdm2 is best known as a critical negative regulator of p53, in the next set of experiments, we analyzed the impact of the observed USP48 mediated Mdm2 stabilization on cellular p53 protein levels and p53 ubiquitination."
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"USP48 promotes Mdm2 stability."
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"Moreover, two previously characterized USP48 mutants lacking deubiquitinase activity were also capable of efficiently stabilizing Mdm2, indicating that USP48 utilizes a non canonical, deubiquitination independent mechanism to promote Mdm2 oncoprotein stability."
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