Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers

Abstract

The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro. In cell-based assays, MDM2 exhibits superior binding to, hyperdegradation of, and increased nuclear exclusion of dimeric p53 when compared with tetrameric wild-type p53. Correspondingly, impairing the hydrophobicity of the newly identified N-terminal MDM2 region leads to p53 stabilization. Interestingly, we found that dimeric mutant p53 is partially unfolded and is a target for ubiquitin-independent degradation by the 20S proteasome. Finally, forcing certain tumor-derived mutant forms of p53 into dimer configuration results in hyperdegradation of mutant p53 and inhibition of p53-mediated cancer cell migration. Gaining insight into different oligomeric forms of p53 may provide novel approaches to cancer therapy.

The Status of p53 Oligomeric and Aggregation States in Cancer

“…Because the p53 tetramerization domain displays a leucine-rich nuclear export signal (NES) that is occluded in active tetramers, but not in dimers, cytosolic p53 is presumably dimeric [47]. In support of that, MDM2 exhibits superior binding to dimers than tetramers [48], reinforcing the scenario of a greater content of p53 dimers in the cytosol. Cytosolic p53 is involved in induction of mitochondrial outer membrane permeabilization (MOMP) [49] which ultimately results in the release of pro-apoptotic effectors and inhibition of autophagy (Reference [46] and citations therein) ( Figure 3B).…”

Circular RNA CDR1as disrupts the p53/MDM2 complex to inhibit Gliomagenesis

“…It is well-known that p53 protein is predominantly degraded through the ubiquitin-proteasome pathway [38]. In consequence, we next examined if p53 ubiquitination is affected by CDR1as.…”

Regulators of Oncogenic Mutant TP53 Gain of Function

“…Oligomerization of TP53 has been implicated in TP53’s DNA binding/transcriptional activity, ubiquitination/degradation, and interactions with TP53 binding partners [165]. Recently, Prives’s group has shown that the N-terminal domain of MDM2 binds to the C-terminal domain of dimer-forming TP53 in which a mutation is inserted in the TP53 oligomerization domain (E343A/K, L344A, L347T, E348A), leading to TP53 degradation [107]. Additionally, the dimer-forming TP53 is prone to MDM2-mediated nuclear export.…”