MDM2 recruitment of lysine methyltransferases regulates p53 transcriptional output

Chen, Lihong; Li, Zhenyu; Zwolińska, Aleksandra; Smith, Matthew A.; Cross, Brittany; Koomen, John M.; Yuan, Zhi-Min; Jenuwein, Thomas; Marine, Jean–Christophe; Wright, Kenneth L.; Chen, Jiandong

doi:10.1038/emboj.2010.140

Cited by 52 publications

(65 citation statements)

References 61 publications

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“…[3][4][5][6][7] However, MDM2 and MDMX genes have become increasingly prominent as key regulators of p53. 36,37 Consistently, overexpression of MDM2 and MDMX were observed in more than 40% of newly diagnosed myelomas using gene expression profile, suggesting the p53 inactivation in these cases (data not shown). Although we do not refute the previous conclusion established by the preponderance of literature, our results suggest that an extrinsic apoptotic signaling pathway is also a possible route for ATO to induce apoptosis.…”

Section: Discussionmentioning

confidence: 49%

Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2

Shi

et al. 2010

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 49%

Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2

Shi

et al. 2010

Cancer Biology & Therapy

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“…Indeed Ehmt2 has been found to bind and methylate lysine 373 of the murine p53 directly. 78 The Ehmt2-dependent methylation of p53 correlates with its inactivation, 79 thereby suggesting that when Ehmt2 function is lost, p53 may become primed for activation. However, it has been recently shown that one splice variant of hEHMT2 is also necessary to attenuate p53's transcriptional activation of its target genes in vitro.…”

Section: Ehmt2 In Cell Cycle Regulationmentioning

confidence: 99%

The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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Epigenetic regulators play a crucial role in neurodevelopment. One such epigenetic complex, Ehmt1/2 (G9a/GLP), is essential for repressing gene transcription by methylating H3K9 in a highly tissue-and temporal-specific manner. Recently, data has emerged suggesting that this complex plays additional roles in regulating the activity of numerous other non-histone proteins. While much is known about the downstream effects of Ehmt1/2 function, evidence is only beginning to come to light suggesting the control of Ehmt1/2 function may be, at least in part, due to context-dependent binding partners. Here we review emerging roles for the Ehmt1/2 complex suggesting that it may play a much larger role than previously recognized, and discuss binding partners that we and others have recently characterized which act to coordinate its activity during early neurodevelopment.

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“…We tested this hypothesis using SUV39H1 as an example because of its efficient MDM2 binding (32). In vitro DNA binding assay showed that coexpression of SUV39H1 with MDM2 partially restored p53 DNA binding function (Fig.…”

Section: Arf Prevents P53 Conformational Change Andmentioning

confidence: 99%

Inhibition of p53 DNA Binding Function by the MDM2 Protein Acidic Domain

Cross

Chen

Qian

et al. 2011

Journal of Biological Chemistry

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MDM2 regulates p53 predominantly by promoting p53 ubiquitination. However, ubiquitination-independent mechanisms of MDM2 have also been implicated. Here we show that MDM2 inhibits p53 DNA binding activity in vitro and in vivo. MDM2 binding promotes p53 to adopt a mutant-like conformation, losing reactivity to antibody Pab1620, while exposing the Pab240 epitope. The acidic domain of MDM2 is required to induce p53 conformational change and inhibit p53 DNA binding. Alternate reading frame binding to the MDM2 acidic domain restores p53 wild type conformation and rescues DNA binding activity. Furthermore, histone methyl transferase SUV39H1 binding to the MDM2 acidic domain also restores p53 wild type conformation and allows p53-MDM2-SUV39H1 complex to bind DNA. These results provide further evidence for an ubiquitination-independent mechanism of p53 regulation by MDM2 and reveal how MDM2-interacting repressors gain access to p53 target promoters and repress transcription. Furthermore, we show that the MDM2 inhibitor Nutlin cooperates with the proteasome inhibitor Bortezomib by stimulating p53 DNA binding and transcriptional activity, providing a rationale for combination therapy using proteasome and MDM2 inhibitors.The tumor suppressor protein p53 encodes a transcription factor that plays a critical role in preventing malignant transformation by inducing cell cycle arrest, DNA repair, or apoptosis in response to various types of damage. Mutations or deletions in the p53 gene occur in over 50% of all human cancers, often in the centrally located sequence-specific DNA-binding domain, resulting in the unfolding and accumulation of p53 in the nucleus (1-3). The p53 core domain has poor thermostability at physiological temperatures and can undergo spontaneous denaturation (4 -6). Changes in p53 conformation can inhibit the ability of p53 to induce expression of its downstream transcriptional targets (7,8).p53 is maintained at low levels in unstressed cells with a short half-life. This is mainly achieved through the ability of MDM2 to bind p53 and act as an ubiquitin E3 ligase to promote its proteasomal degradation (9, 10). MDM2 is also a transcriptional target of p53, forming an auto-regulatory feedback loop (11,12). The importance of MDM2 in the regulation of p53 is highlighted by the fact that mice deficient in MDM2 are embryonic lethal, whereas mice deficient for both MDM2 and p53 are viable (13,14). MDMX, a p53 binding partner with sequence homology to MDM2, is also an essential negative regulator of p53 (15). Unlike MDM2, MDMX lacks ubiquitin ligase activity and is unable to target p53 for proteasomal degradation (16,17). Recent studies suggest that MDMX is a bona fide p53 transcriptional target in certain cell types (17, 18). MDMX can bind to p53 N-terminal transactivation domain and inhibit p53 transcription of target genes (19). MDMX-null mice are embryonically lethal despite expression of MDM2, suggesting a unique role for MDMX in the regulation of p53 (20). The prevailing view is that MDMX mainly functions by re...

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MDM2 recruitment of lysine methyltransferases regulates p53 transcriptional output

Cited by 52 publications

References 61 publications

Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2

Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2

The expanding role of the Ehmt2/G9a complex in neurodevelopment

Inhibition of p53 DNA Binding Function by the MDM2 Protein Acidic Domain

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