Functional analysis and consequences of Mdm2 E3 ligase inhibition in human tumor cells

Wade, Mark; Li, Yao-Cheng; Matani, Anand; Braun, Simon M. G.; Milanesi, Francesca; Rodewald, Luo Wei; Wahl, Geoffrey M.

doi:10.1038/onc.2011.625

Cited by 21 publications

(16 citation statements)

References 46 publications

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“…Interestingly, the upgregulation of Hdm2 combined with the inhibition of the interaction between p53 and Hdm2/HdmX also leads to the downregulation of HdmX likely mediated by the E3-ligase activity of the Hdm2-HdmX complex. 40 …”

Section: Resultsmentioning

confidence: 99%

In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide

Ji¹,

Majumder

Millard³

et al. 2013

J. Am. Chem. Soc.

206

314

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The overexpression of Hdm2 and HdmX is a common mechanism used by many tumor cells to inactive the p53 tumor suppressor pathway promoting cell survival. Targeting Hdm2 and HdmX has emerged as a validated therapeutic strategy for treating cancers with wild-type p53. Small linear peptides mimicking the N-terminal fragment of p53 have been shown to be potent Hdm2/HdmX antagonists. The potential therapeutic use of these peptides, however, is limited by their poor stability and bioavailability. Here, we report the engineering of the cyclotide MCoTI-I to efficiently antagonize intracellular p53 degradation. The resulting cyclotide MCo-PMI was able to bind with low nanomolar affinity to both Hdm2 and HdmX, showed high stability in human serum and was cytotoxic to wild-type p53 cancer cell lines by activating the p53 tumor suppressor pathway both in vitro and in vivo. These features make the cyclotide MCoTI-I an optimal scaffold for targeting intracellular protein-protein interactions.

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Section: Resultsmentioning

confidence: 99%

In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide

Ji¹,

Majumder

Millard³

et al. 2013

J. Am. Chem. Soc.

206

314

View full text Add to dashboard Cite

show abstract

“…1A). Mutagenesis experiments have previously identified residues of MDM2 RING domain involved in the ubiquitin ligase activity of the complex (24,(29)(30)(31). Among these, F490, located at the C-terminus of MDM2, forms a hydrophobic patch at the interface of the complex with residues L433 and I489 of MDM4, and L430 and A434 of MDM2 (Fig.…”

Section: Characterization Of the Mdm2-mdm4 Interaction Interfacementioning

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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“…The N-terminal hydrophobic pocket of MDM2 binds to p53 and thereby inhibits the transcription of p53 target genes. Additionally, the C-terminus of MDM2 contains a RING domain with intrinsic ubiquitin E3 ligase activity [39]. By recruiting E2 ubiquitin conjugating enzyme(s), MDM2 acts as an E3 ubiquitin ligase that facilitates the export of p53 from the nucleus to the cytoplasm and targets p53 for ubiquitin-dependent proteasome degradation.…”

Section: Mdm2 (Hdm2) E3 Ubiquitin Ligasementioning

confidence: 99%

E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma

et al. 2015

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Melanomas are highly proliferative and invasive, and are most frequently metastatic. Despite many advances in cancer treatment over the last several decades, the prognosis for patients with advanced melanoma remains poor. New treatment methods and strategies are necessary. The main hallmark of cancer is uncontrolled cellular proliferation with alterations in the expression of proteins. Ubiquitin and ubiquitin-related proteins posttranslationally modify proteins and thereby alter their functions. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. E3 ligases, the most specific enzymes of ubiquitination system, participate in the turnover of many key regulatory proteins and in the development of cancer. E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others) are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas.

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Functional analysis and consequences of Mdm2 E3 ligase inhibition in human tumor cells

Cited by 21 publications

References 46 publications

In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide

In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide

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

E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma

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