The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2)
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Paula M. Hauck1, Eric R. Wolf2, David J. Olivos III1, Ciaran P. McAtarsney1 and Lindsey D. Mayo1,2,3
1Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indianapolis, Indiana, 46202, United States of America
2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America
3Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America
Lindsey D. Mayo, email: [email protected]
Keywords: MdmX; Mdm2; neddylation; MLN4924; ATM
Received: July 19, 2017 Accepted: October 05, 2017 Published: November 06, 2017
Mouse double minute 2 (Mdm2) and MdmX dimerize in response to low levels of genotoxic stress to function in a ubiquitinating complex, which signals for destabilization of p53. Under growth conditions, Mdm2 functions as a neddylating ligase, but the importance and extent of MdmX involvement in this process are largely unknown. Here we show that when Mdm2 functions as a neddylating enzyme, MdmX is stabilized. Furthermore, we demonstrate that under growth conditions, MdmX enhances the neddylation activity of Mdm2 on p53 and is a substrate for neddylation itself. Importantly, MdmX knockdown in MCF-7 breast cancer cells resulted in diminished neddylated p53, suggesting that MdmX is important for Mdm2-mediated neddylation. Supporting this finding, the lack of MdmX in transient assays or in p53/MdmX-/- MEFs results in decreased or altered neddylation of p53 respectively; therefore, MdmX is a critical component of the Mdm2-mediated neddylating complex. c-Src is the upstream activator of this Mdm2-MdmX neddylating pathway and loss of Src signaling leads to the destabilization of MdmX that is dependent on the RING (Really Interesting New Gene) domain of MdmX. Treatment with a small molecule inhibitor of neddylation, MLN4924, results in the activation of Ataxia Telangiectasia Mutated (ATM). ATM phosphorylates Mdm2, converting Mdm2 to a ubiquitinating enzyme which leads to the destabilization of MdmX. These data show how distinct signaling pathways engage neddylating or ubiquitinating activities and impact the Mdm2-MdmX axis.
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