HDMX Folds the Nascent p53 mRNA following Activation by the ATM Kinase

Malbert-Colas, Laurence; Ponnuswamy, Anand; Olivares‐Illana, Vanesa; Tournillon, Anne-Sophie; Naski, Nadia; Fåhræus, Robin

doi:10.1016/j.molcel.2014.02.035

Cited by 45 publications

(55 citation statements)

References 38 publications

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“…Additionally, HDMX is a substrate of HDM2 E3 ligase activity (33,34). The HDMX(S403D) mutant has, like HDM2, been shown to act as an ATM phosphomimetic (16). First, we tested if the HDMX-HDM2 interaction changes after ATM-mediated phosphorylation on HMD2 and HDMX.…”

Section: Resultsmentioning

confidence: 99%

“…One of the mechanisms by which HDM2-mediated suppression of p53 is prevented following DNA damage involves ATM-mediated phosphorylation of p53 on serine 15, releasing it from the HDM2 interaction (11)(12)(13)). An additional mechanism to ensure optimal levels of p53 protein after genotoxic stress is also mediated by ATM and relates to phosphorylation of HDM2 at S395 and HDMX at S403 and not only stimulates p53 synthesis but also prevents its degradation (15,16). Under the same conditions, HDMX is rapidly degraded by HDM2 (33,34).…”

Section: Discussionmentioning

confidence: 99%

“…HMDX assists HMD2-mediated degradation of p53 under normal conditions and switches to support HMD2-mediated induction of p53 synthesis during genotoxic stress (9,15). This switch in activity is ATM dependent via phosphorylation on serine 403, which allows HMDX to bind the nascent p53 mRNA and form an RNA platform to which HMD2 binds (16). Hence, HDM2 and HDMX are functionally dependent on each other during both the downregulation of p53 under normal conditions and the upregulation of p53 following ATM activation (3-5, 9, 17, 18).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Another example is Mdm2 which primarily acts as a negative regulator of p53 establishing homeostasis in the DNA damage response (DDR). However, recently published studies [19,20] show that following ATM-dependent phosphorylation of Mdm2, the phosphorylated Mdm2 may not target p53 for degradation but rather it enhances p53 synthesis. This is achieved by binding of Mdm2 to the nascent p53 mRNA which, passing likely through the nucleolus, changes Mdm2 to a positive regulator of p53.…”

Section: Spatial Model For P53mentioning

confidence: 99%

Diverse spatio-temporal dynamical patterns of p53 and cell fate decisions

Clairambault¹,

Elias²

2016

AIP Conference Proceedings

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“…C-terminal RING domain of HDMX to the nascent p53 mRNA to trigger p53 synthesis (Malbert-Colas et al, 2014). Increasingly it is being realized that adhesion between cancer cells and extracellular matrix (ECM) proteins, is an initial step of metastasis.…”

Section: Introductionmentioning

confidence: 99%

Recently Emerging Signaling Landscape of Ataxia-Telangiectasia Mutated (ATM) Kinase

Farooqı

Attar²,

Arslan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Asian Pac J Cancer Prev, 15 (16), 6485-6488 IntroductionResearch over decades has gradually and sequentially provided near complete resolution of DNA damage signaling and it is now known that DNA damage repair pathway consists of protein network that is highly branched, tightly regulated and well orchestrated. Ataxiatelangiectasia mutated kinase (ATM), ATR and DNAPKcs are members of phosphoinositide-3-kinase-related protein kinase (PIKK) family. It is evident that DNA damage mediated activation of PIKK family members ATM, ATR and DNA-PKcs is further systematically categorized into modes of repair including homologous recombination (HR) and non-Homologous End Joining (NHEJ).Emerging lines of evidence reveal that ATM is a master regulator of DNA damage signaling and gatekeeper of genome integrity. It has lately been shown that ATM-mediated mitotic arrest-deficient protein 1 (Mad1) phosphorylation at Serine 214 induced homodimerization of Mad1 and its heterodimerization with Mad2. These mechanisms were noted to be necessary for chromosomal stability (Yang et al., 2014). Hepatocyte nuclear factor-1 alpha (HNF1α) is also phosphorylated by ATM at Ser249 AbstractResearch over the years has progressively and sequentially provided near complete resolution of regulators of the DNA repair pathways which are so important for cancer prevention. Ataxia-telangiectasia mutated kinase (ATM), a high-molecular-weight PI3K-family kinase has emerged as a master regulator of DNA damage signaling and extensive cross-talk between ATM and downstream proteins forms an interlaced signaling network. There is rapidly growing scientific evidence emphasizing newly emerging paradigms in ATM biology. In this review, we provide latest information regarding how oxidative stress induced activation of ATM can be utilized as a therapeutic target in different cancer cell lines and in xenografted mice. Moreover, crosstalk between autophagy and ATM is also discussed with focus on how autophagy inhibition induces apoptosis in cancer cells.

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HDMX Folds the Nascent p53 mRNA following Activation by the ATM Kinase

Cited by 45 publications

References 38 publications

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

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

Diverse spatio-temporal dynamical patterns of p53 and cell fate decisions

Recently Emerging Signaling Landscape of Ataxia-Telangiectasia Mutated (ATM) Kinase

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