Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay

Herman, Ariel G.; Hayano, Miki; Poyurovsky, Masha V.; Shimada, Kenichi; Skouta, Rachid; Prives, Carol; Stockwell, Brent R.

doi:10.1158/2159-8290.cd-11-0104

Cited by 85 publications

(81 citation statements)

References 54 publications

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“…Data obtained earlier in other mouse models, also points out to the idea that the response to acute DNA damage by the induction of apoptosis might differ from the tumor suppression pathway evoked by p53 in response to oncogene activation [90]. It should be noted, however, that the transcriptional transactivation function of p53 is necessary for tumor suppression, since transactivation-dead mutant p53 25,26,53,54 (carrying mutations in transactivation domain 1, L25Q;W26S, as well as inactivating mutations in transactivation domain 2, F53Q;F54S) was completely unable to suppress carcinogenesis in several models [91]. Expression of another p53 mutant defective in the induction of pro-apoptotic target genes and apoptosis -p53 RR mutated at residue E177 (corresponding to human E180 and preventing cooperative DNA binding by p53) -lead to an increased tumor incidence in mice compared to control wild type mice.…”

Section: Involvement Of Non-canonical P53 Functions In Tumor Suppressmentioning

confidence: 87%

Wild type p53 reactivation: From lab bench to clinic

Selivanova

2014

FEBS Letters

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Keywords: p53 Small molecule Mdm2 MdmX Apoptosis ROS a b s t r a c tThe p53 tumor suppressor is the most frequently inactivated gene in cancer. Several mouse models have demonstrated that the reconstitution of the p53 function suppresses the growth of established tumors. These facts, taken together, promote the idea of p53 reactivation as a strategy to combat cancer. This review will focus on recent advances in the development of small molecules which restore the function of wild type p53 by blocking its inhibitors Mdm2 and MdmX or their upstream regulators and discuss the impact of different p53 functions for tumor prevention and tumor eradication. Finally, the recent progress in p53 research will be analyzed concerning the role of p53 cofactors and cellular environment in the biological response upon p53 reactivation and how this can be applied in clinic.

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Section: Involvement Of Non-canonical P53 Functions In Tumor Suppressmentioning

confidence: 87%

Wild type p53 reactivation: From lab bench to clinic

Selivanova

2014

FEBS Letters

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“…In fact, smallmolecule inhibitors of MDM2-mediated ubiquitinating activity, have shown unintended activities towards other RING finger E3 ligases (49,50).…”

Section: Discussionmentioning

confidence: 99%

Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy

et al. 2015

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Restoration of wild-type p53 tumor suppressor function has emerged as an attractive anticancer strategy. Therapeutics targeting the two p53-negative regulators, MDM2 and MDM4, have been developed, but most agents selectively target the ability of only one of these molecules to interact with p53, leaving the other free to operate. Therefore, we developed a method that targets the activity of MDM2 and MDM4 simultaneously based on recent studies indicating that formation of MDM2/MDM4 heterodimer complexes are required for efficient inactivation of p53 function. Using computational and mutagenesis analyses of the heterodimer binding interface, we identified a peptide that mimics the MDM4 C-terminus, competes with endogenous MDM4 for MDM2 binding, and activates p53 function. This peptide induces p53-dependent apoptosis in vitro and reduces tumor growth in vivo. Interestingly, interfering with the MDM2/ MDM4 heterodimer specifically activates a p53-dependent oxidative stress response. Consistently, distinct subcellular pools of MDM2/MDM4 complexes were differentially sensitive to the peptide; nuclear MDM2/MDM4 complexes were particularly highly susceptible to the peptide-displacement activity. Taken together, these data identify the MDM2/MDM4 interaction interface as a valuable molecular target for therapeutic reactivation of p53 oncosuppressive function.

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“…It appears that cellular signaling pathways activate p53 mainly by regulating the AD-RING complex. The MDM2 RING domain has become an interesting target of recent drug discovery efforts (59,60). Strategies that activate p53 in tumors without inducing genotoxic damage or that prevent p53 activation in normal tissues may have therapeutic benefits in the treatment of tumors with wild-type or mutant p53 (7,61).…”

Section: Discussionmentioning

confidence: 99%

Autoactivation of the MDM2 E3 Ligase by Intramolecular Interaction

Qian

Song

Chen

2014

Molecular and Cellular Biology

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The RING domain ubiquitin E3 ligase MDM2 is a key regulator of p53 degradation and a mediator of signals that stabilize p53. The current understanding of the mechanisms by which MDM2 posttranslational modifications and protein binding cause p53 stabilization remains incomplete. Here we present evidence that the MDM2 central acidic region is critical for activating RING domain E3 ligase activity. A 30-amino-acid minimal region of the acidic domain binds to the RING domain through intramolecular interactions and stimulates the catalytic function of the RING domain in promoting ubiquitin release from charged E2. The minimal activation sequence is also the binding site for the ARF tumor suppressor, which inhibits ubiquitination of p53. The acidic domain-RING domain intramolecular interaction is modulated by ATM-mediated phosphorylation near the RING domain or by binding of ARF. These results suggest that MDM2 phosphorylation and association with protein regulators share a mechanism in inhibiting the E3 ligase function and stabilizing p53 and suggest that targeting the MDM2 autoactivation mechanism may be useful for therapeutic modulation of p53 levels.A unique feature of the p53 tumor suppressor is its stabilization after exposure to many stress signals. This leads to the induction of numerous transcriptional targets that inhibit cell cycle progression, induce apoptosis, and regulate energy metabolism (1). The MDM2 and MDMX proteins are responsible for establishing the dynamic features of the p53 pathway. MDM2 is a RING domain ubiquitin (Ub) E3 ligase for p53 that promotes p53 degradation (2, 3). Mouse models provided strong evidence that MDM2 is indispensable for controlling p53 activity at all stages of life (4-6). The stabilization of p53 by small-molecule inhibitors that disrupt p53-MDM2 binding also confirmed that MDM2 is a major regulator of p53 turnover (7,8). MDM2-p53 disruptors have antitumor activity in animal models, and their potential as cancer drugs is currently being tested in the clinic (9).Numerous stress signals have been shown to cause p53 accumulation, mainly by inhibiting its degradation. MDM2 promotes p53 degradation by forming a stable complex through N-terminal domains. The MDM2 C-terminal RING domain recruits ubiquitin-conjugating enzyme E2, which performs a covalent modification of p53 lysine residues (10, 11). The major E2 isoforms involved in MDM2-mediated p53 ubiquitination in cells belong to the UbcH5 family (12). The MDM2-UbcH5 combination promotes the synthesis of mainly K48-linked polyubiquitin chains on p53 that target p53 for degradation by the 26S proteasome. MDM2-mediated ubiquitination of p53 is inhibited by multiple mechanisms. Phosphorylation of the p53 N terminus after DNA damage reduces MDM2 binding and contributes to p53 activation (13,14). DNA damage also induces ATM-dependent phosphorylation of MDM2, which inhibits RING domain dimerization and p53 polyubiquitination (15-17). Oncogene activation induces the expression of ARF, which binds to MDM2 and inhibits p53 ubiquitina...

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Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay

Cited by 85 publications

References 54 publications

Wild type p53 reactivation: From lab bench to clinic

Wild type p53 reactivation: From lab bench to clinic

Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy

Autoactivation of the MDM2 E3 Ligase by Intramolecular Interaction

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