MDM2’s social network

Fåhræus, Robin; Olivares‐Illana, Vanesa

doi:10.1038/onc.2013.410

Cited by 83 publications

(89 citation statements)

References 146 publications

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“…The Morris water maze test was performed as described (62). Adult 4-to 6-month-old KO and WT litter-PSD-95 associates with MDM2, an E3 ubiquitin ligase that mediates ubiquitination and degradation of PSD-95 and regulates the function of many cancer-related proteins (34,51,52). Here, for the first time to our knowledge, we demonstrate a novel protein-protein interaction between BAI1 and MDM2, which establishes BAI1 as a novel upstream regulator of the MDM2-PSD-95 interaction and possibly of other MDM2 targets, including the p53 and Rb tumor suppressors (51,52).…”

Section: Methodsmentioning

confidence: 99%

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

Zhu¹,

Li²,

Swanson³

et al. 2015

J. Clin. Invest.

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Section: Methodsmentioning

confidence: 99%

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

Zhu¹,

Li²,

Swanson³

et al. 2015

J. Clin. Invest.

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“…In cancers retaining wild-type (wt) p53, protein function is limited by MDM2, the primary negative regulator of p53. Inhibition of p53 by MDM2 is achieved via suppression of transcriptional activity, promotion of cytoplasmic export, and/or protein degradation (3).…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

Werner

Huang

Francis

et al. 2015

Molecular Cancer Therapeutics

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MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of gH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/ or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.

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“…he activity of the RING-E3 ubiquitin ligase HDM2 is tightly regulated by posttranslational modifications and protein-protein interactions that control its subcellular localization and interacting partners (1,2). The best-characterized activity of HMD2 is the N-terminal interaction between its hydrophobic pocket and the conserved BOX-I domain of p53, which under normal cellular conditions promotes p53 polyubiquitination.…”

mentioning

confidence: 99%

Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions

Medina-Medina

García-Beltrán

Mora

et al. 2016

Molecular and Cellular Biology

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c HDM2 and HDMX are key negative regulatory factors of the p53 tumor suppressor under normal conditions by promoting its degradation or preventing its trans activity, respectively. It has more recently been shown that both proteins can also act as positive regulators of p53 after DNA damage. This involves phosphorylation by ATM on serine residues HDM2(S395) and HDMX(S403), promoting their respective interaction with the p53 mRNA. However, the underlying molecular mechanisms of how these phosphorylation events switch HDM2 and HDMX from negative to positive regulators of p53 is not known. Our results show that these phosphorylation events reside within intrinsically disordered domains and change the conformation of the proteins. The modifications promote the exposition of N-terminal interfaces that support the formation of a new HDMX-HDM2 heterodimer independent of the C-terminal RING-RING interaction. The E3 ubiquitin ligase activity of this complex toward p53 is prevented by the p53 mRNA ligand but, interestingly, does not affect the capacity to ubiquitinate HDMX and HDM2. These results show how ATM-mediated modifications of HDMX and HDM2 switch HDM2 E3 ubiquitin ligase activity away from p53 but toward HDMX and itself and illustrate how the substrate specificity of HDM2 E3 ligase activity is regulated.T he activity of the RING-E3 ubiquitin ligase HDM2 is tightly regulated by posttranslational modifications and protein-protein interactions that control its subcellular localization and interacting partners (1, 2). The best-characterized activity of HMD2 is the N-terminal interaction between its hydrophobic pocket and the conserved BOX-I domain of p53, which under normal cellular conditions promotes p53 polyubiquitination. The nonredundant HDM2 paralogue HDMX (also called HDM4) is, like HDM2, upregulated in human cancers (3)(4)(5). Despite the similarity with the C-terminal RING domain of HDM2 (approximately 75%), HDMX does not harbor E3 ubiquitin ligase activity toward p53, and its negative activity is instead linked to suppression of p53 trans activity. Mice lacking either mdm2 (the hdm2 mouse orthologous) or mdmx (the hdmx mouse orthologous) die early during development in a p53-dependent manner (6-8). It has been shown more recently that HDMX assists HDM2-mediated degradation of p53 by stabilizing HDM2 via a C-terminal RING-RING interaction and also by promoting HMD2-mediated polyubiquitination of p53 in the cytoplasm (9, 10).The ataxia telangiectasia mutated (ATM) kinase is a key regulator of p53 activity during the double-stranded DNA damage response that helps to induce p53 expression and activity. The direct and indirect phosphorylation of residues within the p53 BOX-I domain of p53 prevents the interaction with HDM2 and is linked to an increase in p53 activity (11-13). The phosphorylation on HDM2 at serine 395 (394 in mouse MDM2) is crucial for p53 stabilization, and animals carrying the S394A mutation have an impaired response to irradiation (14). The corresponding mutation in the human protein prevents ...

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MDM2’s social network

Cited by 83 publications

References 146 publications

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors

Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions

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