The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2)

Hauck, Paula M.; Wolf, Eric R.; Olivos, David J.; McAtarsney, Ciaran P.; Mayo, Lindsey D.

doi:10.18632/oncotarget.22320

Cited by 5 publications

(6 citation statements)

References 48 publications

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“…Using an in vitro neddylation reaction with GST-VHL, His-Mdm2, and His-Src, Mdm2 neddylated VHL, and this activity was enhanced with Src ( Figure 3E ), as previously published [ 16 ]. In accordance with previously published data, the addition of MdmX to this reaction also increased the neddylation of VHL ( Figure S2C ) [ 27 ]. It has been shown that Src is phosphorylated at Y416 in response to hypoxia, and we verified this in our cells ( Figure 3F ) [ 28 ].…”

Section: Resultssupporting

confidence: 92%

Mdm2-mediated neddylation of pVHL blocks the induction of antiangiogenic factors

et al. 2020

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Mutations in the tumor suppressor TP53 are rare in renal cell carcinomas. p53 is a key factor for inducing anti-angiogenic genes and RCC are highly vascularized, which suggests that p53 is inactive in these tumors. One regulator of p53 is the Mdm2 oncogene, which is correlated with high-grade, metastatic tumors. However, the sole activity of Mdm2 is not just to regulate p53, but it can also function independent of p53 to regulate the early stages of metastasis. Here, we report that the oncoprotein Mdm2 can bind directly to the tumor suppressor VHL, and conjugate nedd8 to VHL within a region that is important for the p53-VHL interaction. Nedd8 conjugated VHL is unable to bind to p53 thereby preventing the induction of anti-angiogenic factors. These results highlight a previously unknown oncogenic function of Mdm2 during the progression of cancer to promote angiogenesis through the regulation of VHL. Thus, the Mdm2-VHL interaction represents a pathway that impacts tumor angiogenesis.

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Section: Resultssupporting

confidence: 92%

Mdm2-mediated neddylation of pVHL blocks the induction of antiangiogenic factors

et al. 2020

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“…However, we did not observe any change in its expression upon the neddylation blockade ( Figure 5 A). Pevonedistat can also enhance the ubiquitination activity of MDM2, which has been reported to target both Slug and MDMX [ 23 , 24 ]. Nevertheless, we did not observe any change in MDMX levels in our cells upon MLN4924 treatment ( Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

“…The authors suggested E3 ligase FBXO11 as a regulator of Slug degradation upon MLN4924 treatment; however, we did not observe any change in its expression in our cell models. Pevonedistat was also reported to enhance the ubiquitination activity of MDM2, which targets both Slug and MDMX [ 23 , 24 ]. Nevertheless, we did not observe any change in MDMX levels upon the neddylation blockade in our cell models, except in C4-2 cells.…”

Section: Discussionmentioning

confidence: 99%

Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade

Mičková

Kharaishvili

Kurfürstová

et al. 2021

IJMS

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Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.

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“…Several evidences suggest that neddylation, promoted by Mdm2, regulates p53 signaling at different levels. Under DNA damage conditions, the phosphorylation of Mdm2 and MdmX by c-Abl promotes the association of the heterodimer, with Mdm2 acting as a ubiquitinating enzyme that destabilizes MdmX resulting in p53 stabilization [82][83][84]. On the contrary, in growing conditions under c-Src activity, Mdm2 acts as neddylating enzyme that neddylates p53, Mdm2 itself, and MdmX [84,85].…”

Section: The Mdm2/p53 Pathwaymentioning

confidence: 99%

“…Under DNA damage conditions, the phosphorylation of Mdm2 and MdmX by c-Abl promotes the association of the heterodimer, with Mdm2 acting as a ubiquitinating enzyme that destabilizes MdmX resulting in p53 stabilization [82][83][84]. On the contrary, in growing conditions under c-Src activity, Mdm2 acts as neddylating enzyme that neddylates p53, Mdm2 itself, and MdmX [84,85]. Neddylation of p53 prevents the nuclear translocation and inhibits p53 transcriptional activity; in contrast the neddylation-resistant mutants retain the transcriptional activity [59].…”

Section: The Mdm2/p53 Pathwaymentioning

confidence: 99%

New Insights into the Mechanisms Underlying NEDD8 Structural and Functional Specificities

Santonico¹

2019

Ubiquitin Proteasome System - Current Insights Into Mechanism Cellular Regulation and Disease

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Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins are small polypeptides that are conjugated to substrates affecting their activity and stability. Cells encode "receptors" containing Ub-/Ubl-binding domains that interpret and translate each modification into appropriate cellular responses. Among the different Ubls, NEDD8, which is the ubiquitin's closest relative, retains many of the structural determinants that enable ubiquitin the ability to target proteins to degradation. Nevertheless, the direct involvement of NEDD8 conjugation to proteasome recruitment has been proved only in a few cases. To date, well-defined major NEDD8 substrates are primarily members of the cullin family, and cullin neddylation does not appear to mark these proteins for degradation. Various studies have demonstrated that selectivity between ubiquitin and NEDD8 is guaranteed by small but substantial differences. Nevertheless, several issues still need to be addressed, mainly concerning which interaction surfaces mediate NEDD8 function and what domains recognize them. Recently, two novel domains identified in KHNYN and N4BP1 proteins have shed new light on this research area. Here, I discuss some recent reports that contributed to shed light on the mechanisms underlining the discrimination between ubiquitin and NEDD8. Understanding the details of these molecular mechanisms represents a prominent facet for the identification of new therapeutic targets.

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The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2)

Cited by 5 publications

References 48 publications

Mdm2-mediated neddylation of pVHL blocks the induction of antiangiogenic factors

Mdm2-mediated neddylation of pVHL blocks the induction of antiangiogenic factors

Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade

New Insights into the Mechanisms Underlying NEDD8 Structural and Functional Specificities

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