2012
DOI: 10.1158/1078-0432.ccr-11-2617
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MDM2 Overexpression Deregulates the Transcriptional Control of RB/E2F Leading to DNA Methyltransferase 3A Overexpression in Lung Cancer

Abstract: Purpose: Overexpression of DNA 5 0 -cytosine-methyltransferase 3A (DNMT3A), which silences genes including tumor suppressor genes (TSG), is involved in many cancers. Therefore, we examined whether the transcriptional deregulation of RB/MDM2 pathway was responsible for DNMT3A overexpression and analyzed the therapeutic potential of MDM2 antagonist for reversing aberrant DNA methylation status in lung cancer.Experimental Design: The regulation of DNMT3A expression and TSG methylation status by RB/MDM2 was assess… Show more

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Cited by 47 publications
(47 citation statements)
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“…Indeed, the corresponding genomic regions do not contain easily recognizable p53-binding motifs, suggesting that p53 may be recruited to those regions indirectly through association with other DNA-binding proteins. Repression of DNMTs by p53 has already been reported (Jinawath et al 2005;McCabe et al 2005;Lin et al 2010;Tang et al 2012;Ma et al 2015) and was partly ascribed to the ability of p53 to quench E2F transcriptional activity (Kimura et al 2003;Polager and Ginsberg 2009;Tang et al 2012). Furthermore, p53 transcriptionally induces miR-29, which targets all three DNMT transcripts (Yan et al 2015).…”
Section: Discussionmentioning
confidence: 72%
“…Indeed, the corresponding genomic regions do not contain easily recognizable p53-binding motifs, suggesting that p53 may be recruited to those regions indirectly through association with other DNA-binding proteins. Repression of DNMTs by p53 has already been reported (Jinawath et al 2005;McCabe et al 2005;Lin et al 2010;Tang et al 2012;Ma et al 2015) and was partly ascribed to the ability of p53 to quench E2F transcriptional activity (Kimura et al 2003;Polager and Ginsberg 2009;Tang et al 2012). Furthermore, p53 transcriptionally induces miR-29, which targets all three DNMT transcripts (Yan et al 2015).…”
Section: Discussionmentioning
confidence: 72%
“…MDM2 may also have a role in the modification of the cellular epigenetic status. For example, MDM2-dependent degradation of RB can increase the levels and activity of the DNA methyltransferase DNMT3A 142 . This is associated with the silencing of tumour suppressor genes, and suggests that targeting this p53-independent function of MDM2 is a potential therapeutic strategy.…”
Section: Figurementioning
confidence: 99%
“…For example, MDM2 is able to affect processes such as DNA synthesis and repair by interaction with DNA polymerase ϵ[50],[51], DHFR[52], centrosome amplification[53] and the MRN DNA complex containing Nbs1[54],[55], etc. Similarly, MDM2 interacts with several proteins such as Rb/E2F-1 complex[55][57], the DNA methyltransferase DNMT3A[58], p107[59], MTBP[60],[61], the cyclin kinase inhibitor p21, independently of p53, and drives cell cycle progression (typically S-phase)[62],[63]. In an analogous fashion, the MDM2 oncoprotein interacts with the E2F1/Rb pathway to inhibit apoptosis[55].…”
Section: Mdm2 Bioiogymentioning
confidence: 99%