July Newsletter: Post-translational Regulation of Mdm2, an E3 Ubiquitin Ligase for Tumor Suppressor p53

The ubiquitin E3 ligase Mdm2 (murine double minute 2; human homolog, Hdm2) is well known for its oncogenic activities and as the master regulator of the powerful tumor suppressor p53^1,2. Moreover, Mdm2 may function as an oncogenic protein independent of p53³. Mdm2 is able to inhibit p53-mediated gene expression through two pathways: inhibition of transcriptional activity by direct binding and ubiquitin-mediated degradation via its E3 ligase activity⁴; however, the effectiveness of p53 inhibition by direct Mdm2 binding has been questioned⁵.

Under normal, non-stress conditions, Mdm2 maintains p53 expression and activity at a minimal level to tightly regulate its apoptotic/cell death transcriptional activities. Under conditions of cellular stress, Mdm2-mediated ubiquitination of p53 ceases, allowing p53 to activate transcription of apoptotic genes and those involved in inhibiting cell growth. Much research concludes this is due to Mdm2's auto-inhibition by self-ubiquitination^1-3. However, this story appears to be more complex than originally thought⁵ and involves multiple post-translational modifications (PTMs). Here, we discuss Mdm2's regulation by ubiquitination, SUMOylation, phosphorylation, and acetylation^6-8 (Fig. 1).

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Also included in this newsletter:

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• Related Publications