The alternative translated MDMXp60 isoform regulates MDM2 activity Article uri icon

abstract

  • Isoforms derived from alternative splicing, mRNA translation initiation or promoter usage extend the functional repertoire of the p53, p63 and p73 genes family and of their regulators MDM2 and MDMX. Here we show capindependent translation of an N-terminal truncated isoform of hMDMX, hMDMXp60, which is initiated at the 7th AUG codon downstream of the initiation site for full length hMDMXFL at position C384. hMDMXp60 lacks the p53 binding motif but retains the RING domain and interacts with hMDM2 and hMDMXFL. hMDMXp60 shows higher affinity for hMDM2, as compared to hMDMXFL. In vitro data reveal a positive cooperative interaction between hMDMXp60 and hMDM2 and in cellulo data show that low levels of hMDMXp60 promote degradation of hMDM2 whereas higher levels stabilize hMDM2 and prevent hMDM2-mediated degradation of hMDMXFL. These results describe a novel alternatively translated hMDMX isoform that exhibits unique regulatory activity toward hMDM2 autoubiquitination. The data illustrate how the N-terminus of hMDMX regulates its C-terminal RING domain and the hMDM2 activity. © 2015 Taylor %26 Francis Group, LLC.

publication date

  • 2015-01-01