Regulation of MDM2 E3 Ligase Activity by Phosphorylation after DNA Damage

Qian, Cheng; Cross, Brittany; Li, Baozong; Chen, Lihong; Li, Zhenyu; Chen, Jiandong

doi:10.1128/mcb.05553-11

Cited by 62 publications

(69 citation statements)

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“…Mdm4 loss leads to a p53-dependent embryo-lethal phenotype (Parant et al 2001;Migliorini et al 2002). While Mdm2 forms homodimers, it forms heterodimers with Mdm4 more efficiently (Cheng et al 2011). At physiological levels, Mdm2 homodimers predominantly monoubiquitinate p53 and promote its nuclear export.…”

Section: Mdm4 An E4 Ligase?mentioning

confidence: 99%

Limiting the power of p53 through the ubiquitin proteasome pathway

2014

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The ubiquitin proteasome pathway is critical in restraining the activities of the p53 tumor suppressor. Numerous E3 and E4 ligases regulate p53 levels. Additionally, deubquitinating enzymes that modify p53 directly or indirectly also impact p53 function. When alterations of these proteins result in increased p53 activity, cells arrest in the cell cycle, senesce, or apoptose. On the other hand, alterations that result in decreased p53 levels yield tumor-prone phenotypes. This review focuses on the physiological relevance of these important regulators of p53 and their therapeutic implications.

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Section: Mdm4 An E4 Ligase?mentioning

confidence: 99%

Limiting the power of p53 through the ubiquitin proteasome pathway

2014

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“…In the case of MDM2, we showed that phosphorylation of ATM sites near the RING domain inhibits RING homodimerization (8). Furthermore, phosphorylation of the ATM sites inhibits the binding between the MDM2 acidic domain and p53 core domain, suggesting that the MDM2 acidic domain conformation is regulated by the C-terminal ATM sites (8). There is also evidence that the p53 binding pocket of MDM2 allosterically communicates with the acidic domain, such that interaction of the MDM2 N-terminal pocket with the p53 N terminus stimulates a secondsite interaction between the MDM2 acidic domain and the p53 core (50).…”

Section: Discussionmentioning

confidence: 91%

“…9d shows many similarities between MDMX and MDM2 regarding their interdomain relationships. In the case of MDM2, we showed that phosphorylation of ATM sites near the RING domain inhibits RING homodimerization (8). Furthermore, phosphorylation of the ATM sites inhibits the binding between the MDM2 acidic domain and p53 core domain, suggesting that the MDM2 acidic domain conformation is regulated by the C-terminal ATM sites (8).…”

Section: Discussionmentioning

confidence: 93%

“…MDM2 is phosphorylated by ATM, ATR, and C-Abl near the C terminus (32,46,47). MDM2 phosphorylation after DNA damage correlates with reduced dimerization and oligomerization of the RING domain, suggesting that higher-order complex formation is needed for efficient polyubiquitination of p53 (7,8). ATM phosphorylation of MDM2 at S395 also stimulates RNA binding by the RING domain, which has been shown to inhibit E3 ligase activity (11, 28).…”

mentioning

confidence: 99%

“…ATM phosphorylation of MDM2 at S395 also stimulates RNA binding by the RING domain, which has been shown to inhibit E3 ligase activity (11,28). Furthermore, MDM2 phosphorylation by ATM regulates the interaction between the MDM2 acidic domain and p53 DNA binding domain (8). This interaction is important for inducing p53 misfolding and promoting p53 ubiquitination.…”

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confidence: 99%

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Casein Kinase 1α Regulates an MDMX Intramolecular Interaction To Stimulate p53 Binding

Chen

Becker

et al. 2012

Molecular and Cellular Biology

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MDMX is an important regulator of p53 during embryonic development and malignant transformation. Previous studies showed that casein kinase 1␣ (CK1␣) stably associates with MDMX, stimulates MDMX-p53 binding, and cooperates with MDMX to inactivate p53. However, the mechanism by which CK1␣ stimulates MDMX-p53 interaction remains unknown. Here, we present evidence that p53 binding by the MDMX N-terminal domain is inhibited by the central acidic region through an intramolecular interaction that competes for the p53 binding pocket. CK1␣ binding to the MDMX central domain and phosphorylation of S289 disrupts the intramolecular interaction, allowing the N terminus to bind p53 with increased affinity. After DNA damage, the MDMX-CK1␣ complex is disrupted by Chk2-mediated phosphorylation of MDMX at S367, leading to reduced MDMX-p53 binding. Therefore, CK1␣ is an important functional partner of MDMX. DNA damage activates p53 in part by disrupting CK1␣-MDMX interaction and reducing MDMX-p53 binding affinity. The p53 tumor suppressor can be activated by numerous cellular and environmental signals and induces the expression of genes that regulate metabolism, cell growth, division, and apoptosis (49). MDM2 and MDMX are key regulatory proteins that control p53 level and transcriptional activity. Recent studies suggested that the MDM2/MDMX module is largely responsible for enabling p53 to be highly responsive to stress, thus maintaining genomic stability and enhancing cellular and organismal robustness. The importance of p53 in maintaining normal homeostasis is underscored by the frequent p53 mutation or MDM2/MDMX dysregulation in human cancer.MDM2 and MDMX are homologs that bind to p53 with high affinity (31). Genetic analyses showed that both MDM2 and MDMX are essential for controlling p53 activity during embryogenesis (17,35,38). The role of MDMX appears to be less critical than that of MDM2 in adult tissues, as shown by somatic knockout experiments (13,30,55). MDM2 is a classic p53 transcriptional target, forming a negative feedback loop (54). Bona fide p53 binding sites are also found in intron 1 of the human MDMX gene, and p53 activation leads to moderate induction of MDMX transcription (23, 42). Induction of MDMX by p53 was also observed in a mouse model after somatic deletion of casein kinase 1␣ (CK1␣), which triggers oncogenic stress and p53 activation (9). The magnitude of MDMX mRNA induction after p53 activation (1.5 to 3-fold) is moderate compared to that of MDM2 (Ͼ10-fold) and displays cell type specificity. Therefore, MDMX is a p53 target gene that may also provide a negative feedback response to p53 activation.Investigations of p53 activation by DNA damage suggest that phosphorylation of p53, MDM2, and MDMX cooperate to achieve rapid and robust responses. MDM2-p53 binding is essential for degradation of p53 and has been extensively studied. DNA double-strand breaks induce phosphorylation of p53 S15 by DNA-dependent protein kinase (DNA-PK) and ATM (1,33,45). ATM also activates Chk2, which in turn phosphorylates p53...

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Regulation of MDM2 Stability After DNA Damage

Kurokawa

2015

Journal Cellular Physiology

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Cells in our body are constantly exposed to various stresses and threats to their genomic integrity. The tumor suppressor protein p53 plays a critical role in successful defense against these threats by inducing apoptotic cell death or cell cycle arrest. In unstressed conditions, p53 levels and activity must be kept low to prevent lethal activation of apoptotic and senescence pathways. However, upon DNA damage or other stressors, p53 is released from its inhibitory state to induce an array of apoptosis and cell cycle genes. Conversely, inactivation of p53 could promote unrestrained tumor proliferation and failure to appropriately undergo apoptotic cell death, which could, in turn, lead to carcinogenesis. The ubiquitin E3 ligase MDM2 is the most critical inhibitor of p53 that determines the cellular response to various p53-activating agents, including DNA damage. MDM2 activity is controlled by post-translational modifications, especially phosphorylation. However, accumulating evidence suggests that MDM2 is also regulated at the level of protein stability, which is controlled by the ubiquitin-proteasome pathway. Here, we discuss how MDM2 can be regulated in response to DNA damage with particular focus on the regulation of MDM2 protein stability.

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Regulation of MDM2 E3 Ligase Activity by Phosphorylation after DNA Damage

Cited by 62 publications

References 50 publications

Limiting the power of p53 through the ubiquitin proteasome pathway

Limiting the power of p53 through the ubiquitin proteasome pathway

Casein Kinase 1α Regulates an MDMX Intramolecular Interaction To Stimulate p53 Binding

Regulation of MDM2 Stability After DNA Damage

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