HDM2-Binding Partners:  Interaction with Translation Elongation Factor EF1α

Frum, Rebecca A.; Busby, Scott A.; Ramamoorthy, Mahesh; Shabanowitz, Jeffrey; Hunt, Donald F.; Deb, Sumitra

doi:10.1021/pr060584p

Cited by 23 publications

(20 citation statements)

References 37 publications

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“…As MDM2 interacts with several components of the Akt signaling pathway, 8,10 we investigated the ability of endogenous MDM2 to elicit Akt phosphorylation. For this purpose, we generated littermate MDM2 transgenic mice with a p53 þ / þ and p53 À / À background.…”

Section: Resultsmentioning

confidence: 99%

“…9 Apart from its functional interaction with Akt, MDM2 interacts with the translation elongation factor EF1a, which is known to upregulate PI4-kinase and to interact with Akt2. 10 The Akt signaling pathway transmits signals from membrane-bound receptors and regulates cell proliferation, survival and motility, processes that are deregulated during tumorigenesis. 11 Activation of the pathway has been implicated in diminished sensitivity of cancer cells to chemotherapeutic drugs.…”

mentioning

confidence: 99%

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Human oncoprotein MDM2 activates the Akt signaling pathway through an interaction with the repressor element-1 silencing transcription factor conferring a survival advantage to cancer cells

et al. 2012

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The current paradigm states that the Akt signaling pathway phosphorylates the human oncoprotein mouse double minute 2 (MDM2), leading to its nuclear translocation and degradation of the tumor suppressor p53. Here we report a novel Akt signaling pathway elicited by MDM2. Upregulation of endogenous MDM2 promotes, whereas its downregulation diminishes, Akt phosphorylation irrespective of p53 status. MDM2 requires phosphatidylinositol (PI)3-kinase activity for enhancing Akt phosphorylation and upregulates this activity by repressing transcription of the regulatory subunit p85 of PI3-kinase. MDM2 interacts with the repressor element-1 silencing transcription factor (REST), a tumor suppressor that functions by downregulating PI3-kinase activity and Akt phosphorylation, prevents localization of REST on the p85 promoter and represses p85 expression. The deletion mutant of MDM2 capable of upregulating Akt phosphorylation represses p85 expression and interferes with localization of REST on the p85 promoter, whereas the deletion mutant of MDM2 that does not increase Akt phosphorylation cannot perform these functions. Silencing of REST abrogates the ability of MDM2 to upregulate Akt phosphorylation and downregulate p85 expression, implicating the ability of MDM2 to interact with REST in its ability to inhibit p85 expression and activate Akt phosphorylation. Inhibition of MDM2-mediated Akt phosphorylation with an Aktphosphorylation-specific inhibitor abrogates its ability to improve cell survival. Consistently, the Akt phosphorylation function of MDM2 was required for its ability to improve cell survival after treatment with a chemotherapeutic drug. Our report not only unravels a novel signaling pathway that contributes to cell survival but also implicates a p53-independent transcription regulatory function of MDM2 in Akt signaling. The human homolog of the mouse double minute-2 gene product (MDM2) is frequently overexpressed in human sarcomas and carcinomas, and amplification of the mdm2 gene enhances the tumorigenic potential of murine cells, 1,2 implicating the genetic alteration in oncogenesis. MDM2 interacts with several growth suppressors, including the wild-type (WT) tumor suppressor p53, the retinoblastoma susceptibility gene product (Rb) and the growth suppressor p14.1,3 Although these interactions contribute to its oncogenic function, overexpression of MDM2 is thought to induce oncogenesis primarily by inactivating WT p53.MDM2 recognizes the transactivation domain of p53 and inactivates p53-mediated transcriptional activation; 4 it is also an E3 ubiquitin ligase and degrades p53 by targeting it for ubiquitination. 5 Small-molecule anti-MDM2 drugs, such as Nutlin or MDM2-specific silencer RNA, induce apoptosis and drug sensitivity in cell lines harboring WT p53 by elevating p53 levels. 6 Overexpression of MDM2 reduces the chemotherapeutic sensitivity of cancer cells by inactivating and degrading WT p53. 7Cancer cells with mutated p53 often overexpress MDM2, and the prognosis of this group of cancers is worse than th...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Human oncoprotein MDM2 activates the Akt signaling pathway through an interaction with the repressor element-1 silencing transcription factor conferring a survival advantage to cancer cells

et al. 2012

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“…eEF1A1 interacts with the HDM2 gene product at a binding site for eEF1A1 overlaps with that for p53. In normal cells eEF1A1 could promote cell apoptosis by preventing p53 sequestration by HDM2 (Frum et al, 2007). Likely both eEF1A1 and eEF1A2 interacts with the zinc finger protein ZPR1 in response to mitogenic stimuli, redistributing eEF1A1/2 and ZPR1 in the nucleus.…”

Section: Functionmentioning

confidence: 99%

EEF1A1 (eukaryotic translation elongation factor 1 alpha 1)

Scaggiante¹,

Bosutti²

2015

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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“…Western blot analysis was carried out as described previously. 47,48 Antibodies. Antibody against MDM2 (Ab-1 Calbiochem, San Diego, California) was used in 1:100 dilutions.…”

Section: Generation Of Cdna and Quantitative Pcr (Qpcr)mentioning

confidence: 99%

Human Oncoprotein MDM2 Up-regulates Expression of NF- B2 Precursor p100 Conferring a Survival Advantage to Lung Cells

Vaughan

Mohanraj

Singh³

et al. 2011

Genes & Cancer

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The current model predicts that MDM2 is primarily overexpressed in cancers with wild-type (WT) p53 and contributes to oncogenesis by degrading p53. Following a correlated expression of MDM2 and NF-κB2 transcripts in human lung tumors, we have identified a novel transactivation function of MDM2. Here, we report that in human lung tumors, overexpression of MDM2 was found in approximately 30% of cases irrespective of their p53 status, and expression of MDM2 and NF-κB2 transcripts showed a highly significant statistical correlation in tumors with WT p53. We investigated the significance of this correlated expression in terms of mechanism and biological function. Increase in MDM2 expression from its own promoter in transgenic mice remarkably enhanced expression of NF-κB2 compared with its non-transgenic littermates. Knockdown or elimination of endogenous MDM2 expression in cultured non-transformed or lung tumor cells drastically reduced expression of NF-κB2 transcripts, suggesting a normal physiological role of MDM2 in regulating NF-κB2 transcription. MDM2 could up-regulate expression of NF-κB2 transcripts when its p53-interaction domain was blocked with Nutlin-3, indicating that the MDM2-p53 interaction is dispensable for up-regulation of NF-κB2 expression. Consistently, analysis of functional domains of MDM2 indicated that although the p53-interaction domain of MDM2 contributes to the up-regulation of the NFκB2 promoter, MDM2 does not require direct interactions with p53 for this function. Accordingly, MDM2 overexpression in non-transformed or lung cancer cells devoid of p53 also generated a significant increase in the expression of NF-κB2 transcript and its targets CXCL-1 and CXCL-10, whereas elimination of MDM2 expression had the opposite effects. MDM2-mediated increase in p100/NF-κB2 expression reduced cell death mediated by paclitaxel. Furthermore, knockdown of NF-κB2 expression retarded cell proliferation. Based on these data, we propose that MDM2-mediated NF-κB2 up-regulation is a combined effect of p53-dependent and independent mechanisms and that it confers a survival advantage to lung cancer cells.

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HDM2-Binding Partners: Interaction with Translation Elongation Factor EF1α

Cited by 23 publications

References 37 publications

Human oncoprotein MDM2 activates the Akt signaling pathway through an interaction with the repressor element-1 silencing transcription factor conferring a survival advantage to cancer cells

Human oncoprotein MDM2 activates the Akt signaling pathway through an interaction with the repressor element-1 silencing transcription factor conferring a survival advantage to cancer cells

EEF1A1 (eukaryotic translation elongation factor 1 alpha 1)

Human Oncoprotein MDM2 Up-regulates Expression of NF- B2 Precursor p100 Conferring a Survival Advantage to Lung Cells

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