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

Katz, Chen; Low-Calle, Ana Maria; Choe, Joshua H.; Laptenko, Oleg; Tong, David; Joseph-Chowdhury, Jazmine-Saskya N.; Garofalo, Francesca; Zhu, Yuyan; Friedler, Assaf; Prives, Carol

doi:10.1101/gad.304071.117

Cited by 29 publications

(33 citation statements)

References 106 publications

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“…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).…”

Section: P53 Oligomeric Statesmentioning

confidence: 93%

The Status of p53 Oligomeric and Aggregation States in Cancer

et al. 2020

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Despite being referred to as the guardian of the genome, when impacted by mutations, p53 can lose its protective functions and become a renegade. The malignant transformation of p53 occurs on multiple levels, such as altered DNA binding properties, acquisition of novel cellular partners, or associating into different oligomeric states. The consequences of these transformations can be catastrophic. Ongoing studies have implicated different oligomeric p53 species as having a central role in cancer biology; however, the correlation between p53 oligomerization status and oncogenic activities in cancer progression remains an open conundrum. In this review, we summarize the roles of different p53 oligomeric states in cancer and discuss potential research directions for overcoming aberrant p53 function associated with them. We address how misfolding and prion-like amyloid aggregation of p53 seem to play a crucial role in cancer development. The misfolded and aggregated states of mutant p53 are prospective targets for the development of novel therapeutic strategies against tumoral diseases.

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Section: P53 Oligomeric Statesmentioning

confidence: 93%

The Status of p53 Oligomeric and Aggregation States in Cancer

et al. 2020

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“…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.…”

Section: Cdr1as Stabilizes P53 Protein By Suppressing Its Ubiquitinationmentioning

confidence: 99%

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

et al. 2020

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Background Inactivation of the tumor suppressor p53 is critical for pathogenesis of glioma, in particular glioblastoma multiforme (GBM). MDM2, the main negative regulator of p53, binds to and forms a stable complex with p53 to regulate its activity. Hitherto, it is unclear whether the stability of the p53/MDM2 complex is affected by lncRNAs, in particular circular RNAs that are usually abundant and conserved, and frequently implicated in different oncogenic processes. Methods RIP-seq and RIP-qPCR assays were performed to determine the most enriched lncRNAs (including circular RNAs) bound by p53, followed by bioinformatic assays to estimate the relevance of their expression with p53 signaling and gliomagenesis. Subsequently, the clinical significance of CDR1as was evaluated in the largest cohort of Chinese glioma patients from CGGA (n = 325), and its expression in human glioma tissues was further evaluated by RNA FISH and RT-qPCR, respectively. Assays combining RNA FISH with protein immunofluorescence were performed to determine co-localization of CDR1as and p53, followed by CHIRP assays to confirm RNA-protein interaction. Immunoblot assays were carried out to evaluate protein expression, p53/MDM2 interaction and p53 ubiquitination in cells in which CDR1as expression was manipulated. After AGO2 or Dicer was knocked-down to inhibit miRNA biogenesis, effects of CDR1as on p53 expression, stability and activity were determined by immunoblot, RT-qPCR and luciferase reporter assays. Meanwhile, impacts of CDR1as on DNA damage were evaluated by flow cytometric assays and immunohistochemistry. Tumorigenicity assays were performed to determine the effects of CDR1as on colony formation, cell proliferation, the cell cycle and apoptosis (in vitro), and on tumor volume/weight and survival of nude mice xenografted with GBM cells (in vivo). Results CDR1as is found to bind to p53 protein. CDR1as expression decreases with increasing glioma grade and it is a reliable independent predictor of overall survival in glioma, particularly in GBM. Through a mechanism independent of acting as a miRNA sponge, CDR1as stabilizes p53 protein by preventing it from ubiquitination. CDR1as directly interacts with the p53 DBD domain that is essential for MDM2 binding, thus disrupting the p53/MDM2 complex formation. Induced upon DNA damage, CDR1as may preserve p53 function and protect cells from DNA damage. Significantly, CDR1as inhibits tumor growth in vitro and in vivo, but has little impact in cells where p53 is absent or mutated. Conclusions Rather than acting as a miRNA sponge, CDR1as functions as a tumor suppressor through binding directly to p53 at its DBD region to restrict MDM2 interaction. Thus, CDR1as binding disrupts the p53/MDM2 complex to prevent p53 from ubiquitination and degradation. CDR1as may also sense DNA damage signals and form a protective complex with p53 to preserve p53 function. Therefore, CDR1as depletion may play a potent role in promoting tumorigenesis through down-regulating p53 expression in glioma. Our results broaden further our understanding of the roles and mechanism of action of circular RNAs in general and CDR1as in particular, and can potentially open up novel therapeutic avenues for effective glioma treatment.

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“…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.…”

Section: Dimer-forming Mutp53mentioning

confidence: 99%

Regulators of Oncogenic Mutant TP53 Gain of Function

Yamamoto

Iwakuma

2018

Cancers

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The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin ligases, and molecular chaperones, as well as a single nucleotide polymorphism (SNP) and dimer-forming mutations in mutp53.

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

Cited by 29 publications

References 106 publications

The Status of p53 Oligomeric and Aggregation States in Cancer

The Status of p53 Oligomeric and Aggregation States in Cancer

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

Regulators of Oncogenic Mutant TP53 Gain of Function

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