E3 ligase mdm2. 1997; Honda et al.

E3 ligase mdm2. Zou and colleagues demonstrate that MDM2 also has a T cell-intrinsic role that supports Jul 10, 2020 · Targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53. E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. Indeed, many new E3 ligands have been published recently, confirming the druggability of E3 ligases. Genetic studies showing that embryonic Oct 16, 2023 · Proteolysis-targeting chimeras (PROTACs) offer new avenues for drug development. Here we show that Dec 1, 2003 · MDM2 functions as the E3 ligase to ubiquitinate p53 at several lysine residues (10, 11). Since many cancer-related proteins, including both oncogenic and Targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53. Jan 1, 2018 · MDM2 inhibits p53 in two ways; it suppresses the transcriptional activity of p53 through physical binding and it promotes proteasomal degradation of p53 protein as an ubiquitin E3 ligase (Haupt et al. In the past two decades, many MDM2 inhibitors that disrupt MDM2-p53 binding have been discovered and developed. We propose that binders of partner proteins of single-subunit ligases could be repurposed as Jul 6, 2025 · Gene target information for MDM2 - MDM2 proto-oncogene (human). Abstract E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. Reaction conditions will need to be optimized for each specific application. Our previous study suggested that ATM phosphorylation of MDM2 near the C terminus inhibits RING domain oligomerization, resulting in p53 stabilization after DNA damage. The importance of MDM2 E3-ligase-mediated p53 reg-ulation remains controversial. To resolve this, we generated mice with an Mdm2 L466A mutation that specifically compromises E2 Mdm2 E3 ubiquitin ligase-mediated p53 degradation is generally accepted as the major mechanism for p53 regulation; nevertheless, the in vivo significance of this function has not been unequivocally established. This Review discusses the crucial roles of E3 ligases during early mammalian Recombinant Human GST-Mdm2 is a Ubiquitin ligase (E3) that functions downstream of a Ubiquitin-activating (E1) enzyme and a Ubiquitin-conjugating (E2) enzyme to conjugate Ubiquitin to substrate proteins. E3 ubiquitin ligase Mdm2 facilitates β-arrestin ubiquitination, leading to the internalization of G protein–coupled receptors (GPCRs). Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. 2. Nutlins prevent binding of the E3 ligase MDM2 to its substrate, the tumour suppressor p53 [19, 48 – 51]. In turn, MDM2 serves as an E3 ubiquitin ligase for p53, promoting its ubiquitination and degradation (30). MDM2 and MDM4 are key regulators of p53 and function as oncogenes when aberrantly expressed. p53 protein regulates the expression of MDM2 (mouse double-minute 2 protein) E3 ligase and MDMX (double-minute 4 protein), through proteasome-based degradation. Jan 15, 2015 · Here we report biochemical identification of NEDD4-1 as an E3 ligase for Mdm2 that contributes to the regulation of Mdm2 protein stability in cells. We complete this review by posing some questions that might point the way toward future research on this fascinating subject. Oct 4, 2024 · Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Discover more>> Details Name E3 ubiquitin-protein ligase Mdm2 Kind protein Synonyms 2. May 7, 2013 · The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. 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 is a major regulator of p53 by acting as a ubiquitin E3 ligase. As such, targeted inhibition of Mdm2 is being considered as a therapeutic anticancer strategy. The RING domain ubiquitin E3 ligase MDM2 is a key regulator of p53 degradation and a mediator of signals that stabilize p53. The discoveries of MdmX, HAUSP, ARF, COP1, Pirh2, and ARF-BP1 continue to uncover the multiple facets of this pathway. Sep 28, 2020 · Finally, we show that overexpression of pVHL30 and MDM2 together reduces cell metabolic activity and necrosis, suggesting a synergistic effect of these E3 ubiquitin ligases. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. To study these functions physiologically, we generated mice bearing a single-residue substitution (C462A) abolishing the E3 function without affecting p53 binding. The current understanding of the mechanisms by which MDM2 posttranslational modifications and protein binding cause p53 Feb 28, 2019 · The E3 ubiquitin ligase MDM2 is intimately involved in genome instability, but its mechanisms are unclear. The importance of MDM2 E3-ligase-mediated p53 regulation remains controversial. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide … Aug 8, 2014 · Mdm2 E3 ubiquitin ligase-mediated p53 degradation is generally accepted as the major mechanism for p53 regulation; nevertheless, the in vivo significance of this function has not been unequivocally established. Find diseases associated with this biological target and compounds tested against it in bioassay experiments. While therapeutic inhibition of oncogene-encoded kinases has shown clinical success, restoring TS functions remains challenging due to conceptual and technical limitations. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Surprisingly, ligands binding to the hydrophobic cleft of MDM2 do not inhibit its E3-ligase function Our ongoing work focuses on the development of the third generation of MDM2 degraders featuring a novel and achiral ligand for the E3 ligase component cereblon (CRBN). Indeed, several small In particular, in addition to MDM2, we focus on the p53-independent functions of MDMX and the MDM2–MDMX E3 ligase complex, which are relatively less studied in comparison with those of MDM2. MDM-linked dysfunction is associated with an increased risk of oncogenesis, primarily through targeting the tumor suppressor protein … MDM2 regulates p53 degradation by functioning as an E3 ubiquitin ligase. Owing to this, scientists attempt to identify safe and bio This Recombinant Mouse E3 ubiquitin-protein ligase Mdm2 (Mdm2) includes amino acids 1-489aa, features N-terminal 6xHis tag with purity >90% by SDS-PAGE. 1993). May 2, 2025 · The discovery of novel ligands recruiting less explored E3 ligases remains challenging. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls Nov 7, 2024 · Results and Discussion Ubiquitylation of cDNA Displayed p53 Degron As the initial step of the study, we examined if cDNA display molecules incorporating a known degron was ubiquitylated in vitro as expected. The twenty-one-amino-acid-length degron previously found from p53 (PLSSSVPSQKTYQGSYGFRLG) 24, 25 The tumor suppressor p53 plays a prominent role in the protection against cancer. Herein, the discovery of a novel Mouse double minute 2-recruiting Proteolysis-Targeting Chimera is reported, w Finally, we show that overexpression of pVHL30 and MDM2 together reduces cell metabolic activity and necrosis, suggesting a synergistic effect of these E3 ubiquitin ligases. The mechanism of MDM2-mediated ubiquitination of p53 has been analyzed by deconstructing, in vitro, the MDM2-dependent ubiquitination reaction. show that mice expressing only a Mdm2 mutant deficient in E3 ligase activity, yet still able to bind to MdmX, survive and develop normally, but suffer from p53-dependent mortality when exposed to minor stress, providing insight for the Mdm2-p53 autoregulatory loop and how to target it therapeutically. UniProt is the world's leading high-quality, comprehensive and freely accessible resource of protein sequence and functional information. We provide an overview of MDM2 inhibitor … Aug 11, 2014 · Tollini et al. 1997; Kubbutat et al. 1997; Honda et al. Jun 5, 2009 · A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. E3 ubiquitin ligases Feb 1, 2016 · MDM2 is known to induce ubiquitination of several target proteins, with the most well-known target of MDM2 E3 ligase being p53 (refs 36, 42). Over the past 2 decades, the number of studies on ubiquitination has demonstrated explosive growth. Our previous study suggested that ATM phosphorylation of MDM2 near The regulation of p53’s functions by E3 ubiquitin ligases is a complex process that can lead to positive or negative regulation of p53 protein in a context- and cell type-dependent manner. This Review discusses the crucial roles of E3 ligases during early mammalian Jan 25, 2022 · E3 ubiquitin ligases ensure the precise spatiotemporal control of key molecules during important cellular processes. It targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. Given that the MDM2-p53 forms See full list on cytoskeleton. Surprisingly, ligands binding to the hydrophobic cleft of MDM2 do not inhibit its E3-ligase function Aug 3, 2016 · Protein ubiquitylation has important regulatory functions, influencing protein–protein interactions and protein stability. Here, we have generated an Mdm2[Y487A] Ubiquitin modification plays significant roles in protein fate determination, signaling transduction, and cellular processes. Inhibitors disrupting p53 interaction with MDM2/MDM4 are in clinical Jan 13, 2014 · Here we report biochemical identification of NEDD4-1 as an E3 ligase for Mdm2 that contributes to the regulation of Mdm2 protein stability in cells. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide … Oct 4, 2024 · M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Aug 5, 2023 · As a major negative regulator of the tumor suppressor p53, the E3 ligase murine double minute 2 (MDM2) facilitates the degradation of p53 and is often overexpressed in many tumors, which renders many therapeutic agents have been developed to disturb MDM2-p53 interaction, such as RG7112, MI-77301, RG7388, and AMG232 [35]. Full-length MDM2 (MDM2-FL) is best known for targeting wild-type p53 for degradation by the proteasome, but the functions of the many splice variants of MDM2 are under-explored. The RING motif is common in E3 ligases and is responsible for the E3 ligase activity of MDM2 (see Fig. Feb 2, 2023 · Our study was focused on the identification of a potent ubiquitin E3 ligase and how these ubiquitin E3 ligases can be targeted using natural inhibitors. It also has the ability to ubiquitinate itself (12, 13). Abstract Ubiquitination is a key enzymatic post-translational modification that influences p53 stability and function. Central to PROTAC technology are the E3 ligase recruiters, yet only a few of them have been identified due to the lack of ligandable pockets in ligases, especially among single-subunit ligases. There is no question that Mdm2 E3 ubiquitin ligases are important players in cellular processes by ubiquitinating substrate proteins in disease progression such as cancer. Here the authors investigate E3 ligases—key to PROTAC function—and identify candidate targets for cancer Aug 10, 2008 · The E3 ubiquitin ligase Mdm2 is a focal regulator of p53 tumour suppressor activity. p53 can induce transcription of MDM2, generating a negative feedback loop. Overexpression of Mdm2 facilitates tumorigenesis by inactivating p53, and through p53 The HECT E3 Itch (itchy E3 ubiquitin protein ligase) has been shown to be a primary regulator of both proteins by targeting them for ubiquitination-mediated degradation. , 2004; Schneekloth et al. However, it is Feb 1, 2012 · The functional MDM2 E3 ligase can be a MDM2 homodimer or a heterodimer with MDMX (Lee and Gu, 2010; Wade et al. To resolve this, we generated mice with an Mdm2 L466A mutation that specifically compromises E2 interaction May 22, 2009 · MDM2 is an oncogene that is transcriptionally induced by the p53 tumor suppressor. Feb 14, 2017 · We investigated the regulation of MDM2 substrate specificity and found that acetyltransferase p300–mediated acetylation and stabilization of MDM2 are molecular switches that block self-ubiquitination, thereby shifting its E3 ligase activity toward p53. For the discovery of a first-in-class PROTAC for a target of interest, the E3 ligases commonly hijacked remain the Von Hippel-Lindau (VHL) and Cereblon (CRBN) s … Oct 23, 2024 · The E3 ligase UBR5 progressively reduces the concentration of the retinoblastoma protein Rb during G1 to drive proliferation. The N-terminal hydrophobic pocket of Mdm2 binds to p53 and thereby inhibits the transcription of p53 target genes. Upregulation of MDM2 and repression of p53 activity is highly associated with cancer development 43. MDM2 and MDM4 form heterodimer polyubiquitin E3 ligases via thei … Jan 2, 2018 · The activity of p53 is mainly controlled by the ubiquitin E3 ligase Mdm2, which targets p53 for proteasomal degradation. Another compound currently in clinical trials for cancer is the Smac mimetic GDC-0152, which binds to anti-apoptotic proteins (IAPs), inducing IAP self-ubiquitylation and degradation, and consequently apoptosis [52]. MDM2-deficient mice are embryonically lethal due to fatal p53 activation. 1997; Oliner et al. By ubiquitinating the tumor suppressor p53 protein, which leads to its proteasome-mediated destruction, MDM2 limits the tumor-suppressing activity of p53. The importance of MDM2 E3-ligase-mediated Here, we show that MARCH7, a RING domain-containing ubiquitin E3 ligase, physically interacts with Mdm2 and is essential for maintaining the stability of Mdm2. Feb 14, 2017 · Abnormal activation of the oncogenic E3 ubiquitin ligase murine double minute 2 (MDM2) is frequently observed in human cancers. Jul 21, 2006 · The control of p53 ubiquitination by MDM2 provides a model system to define how an E3-ligase functions on a conformationally flexible substrate. Exploration of targeting the ubiquitination pathway offers a potentially promising strategy for precision therapy in Oct 16, 2007 · It is believed that Mdm2 suppresses p53 in two ways: transcriptional inhibition by direct binding, and degradation via its E3 ligase activity. The Dec 30, 2024 · PROTACs have emerged as a therapeutic modality for the targeted degradation of proteins of interest (POIs). Jun 23, 2023 · The E3 ubiquitin-protein ligase activity of MDM2 is easily monitored with a commercial kit containing all required reagents necessary for the ubiquitination of P53 and analysis of apparent E3 ubiquitin ligases are a large family of enzymes that join in a three-enzyme ubiquitination cascade together with ubiquitin activating enzyme E1 and ubiquitin conjugating enzyme E2. Our data demonstrated that the transcription factor HBP1 is a target of MDM2. Additionally, the C-terminus of Mdm2 contains a RING domain with intrinsic ubiquitin E3 ligase activity. It binds p53, promoting its polyubiquitination and degradation, and also controls p53 synthesis. Although early studies have suggested that the onco-protein Mdm2 is the primary E3 ubiquitin ligase for the p53 tumor suppressor, an increasing amount of data suggests that p53 ubiquitination and degradation are more complex than once thought. 5, and deletion of p53 rescued the E3 ubiquitin ligases are a class of enzymes, essential for maintaining the equilibrium of cells by binding ubiquitin molecules to substrates to mark them for destruction. The role of MDMX, an MDM2 homolog that lacks E3 ligase activity, in the regulation of p53 degradation remains incompletely understood and sometime controversial. Mdm2, p53 E3 Ubiquitin Protein Ligase Homolog (Mouse) (MDM2) (AA 1-489) protein (Strep Tag) custom-made MDM2 Origin: Mouse Host: Cell-free protein synthesis (CFPS) Recombinant approximately 70-80 % as determined by SDS PAGE, Western Blot and analytical SEC (HPLC). Here we show that Feb 1, 2016 · Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. 1). To resolve this, we generated mice with an Mdm2 L466A mutation that specifically compromises E2 interaction, abolishing MDM2 E3 ligase activity while preserving its ability to bind MDM4 and suppress p53 transactivation. Jul 23, 2018 · The mouse double minute 2 (MDM2) protein is an E3-ubiquitin ligase recognized for its role as a negative regulator of the tumor suppressor protein p53 [1]. Here, we show that MARCH 7, a RING domain‐containing ubiquitin E3 ligase, physically interacts with Mdm2 and is essential for maintaining the stability of Mdm2. MDM2 activity is controlled by post-translational modifications, especially phosphorylation. We recommend an initial Recombinant Human GST-Mdm2 concentration of 0. (21) The binding of MDM2 to p53 causes the inactivation of p53, leading to the functional loss in p53 activity. Our approach was based on using mutational analysis, pathway studies, and expressional analysis to explore the role of various ubiquitin E3 ligases in GBM. MARCH7 catalyzes Lys 63 -linked polyubiquitination of Mdm2, which impedes Mdm2 autoubiquitination and degradation, thereby leading to the stabilization of Mdm2. The activity of p53 is mainly controlled by the ubiquitin E3 ligase Mdm2, which targets p53 for proteasomal degradation. MDM2 and MDM4 partner to suppress p53 transcriptional transactivation and polyubiquitinate p53 for degradation. Similarly to p53 and HIF-1α, the steady-state levels of p63 and p73 are kept low by constant ubiquitin-dependent degradation in unstressed cells [59, 63 - 69]. The final step of ubiquitylation is catalysed by ubiquitin ligases (E3s Oct 4, 2024 · M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. NEDD4-1 was identified from Jurkat cytosolic fractions using an enzyme-dead Mdm2 mutant protein as a substrate for in vitro E3 ligase assays. Unexpectedly, homozygous mutant mice died before E7. We used MDM2, one of the RING-typed E3 ligases, and p53 substrate pair as a model system. com Jan 26, 2023 · (20) MDM2 acts as a ubiquitin E3 ligase and functions by binding to p53 (tumor suppressor protein). Given that MDM2 and p53 form an auto-regulatory loop, in which p53 undergoes Jun 28, 2013 · The RING domain E3 ubiquitin ligase Mdm2 is the master regulator of the tumor suppressor p53. This confusion Feb 15, 2021 · MDM2 regulates p53 degradation by functioning as an E3 ubiquitin ligase. E3 ubiquitin ligases that ubiquitinate TS proteins for accelerated Jul 21, 2006 · The control of p53 ubiquitination by MDM2 provides a model system to define how an E3-ligase functions on a conformationally flexible substrate. However, the regulation of Mdm2 remains not Feb 14, 2023 · Using HiBiT CRISPR cell line, biochemical methods, and RNA sequencing, we report the potential role of VNPP433-3β, the next generation galeterone analog as molecular glue that brings together AR, the key driver of prostate cancer and MDM2, an E3 ubiquitin ligase leading to ubiquitination and subsequent degradation of f-AR and AR-V7 in prostate Jul 11, 2025 · The phenotypic effect induced by a Proteolysis-Targeting Chimera (PROTAC) can depend on several factors, including the E3 ligase recruited. [7] Mdm2 also acts as an E3 ubiquitin ligase, targeting both itself and p53 for degradation by the proteasome (see also ubiquitin). MDM2 binds and ubiquitinates p53, facilitating it for degradation. In particular, MDM2 has been shown to regulate serine metabolism independently of p53 status in several types of neoplasia, including NSCLC. Indeed, two classes of small molecules that target Mdm2 to reactivate p53 and to induce apoptosis have been discovered so far: the first class comprises inhibitors of Mdm2 E3 ubiquitin ligase and the second class comprises compounds that disrupt Mdm2-p53 binding, as illustrated in Figure 2. Promotes proteasome-dependent Oct 14, 2013 · p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Accessory proteins bind and modulate E3 ubiquitin ligases, adding yet another layer of regulatory control for p53 and its downstream functions. Mar 25, 2021 · The E3 ubiquitin ligase MDM2 inhibits the tumor suppressor p53 and is an important therapeutic target. Herein, the discovery of a novel Mouse double minute 2-recruiting Proteolysis-Targeting Chimera is reported, w Aug 9, 2024 · The phenotypic effect induced by a Proteolysis-Targeting Chimera (PROTAC) can depend on several factors, including the E3 ligase recruited. Collectively, our data show an isoform-specific interaction of pVHL with MDM2, suggesting an interplay between these two E3 ubiquitin ligases. Permits the nuclear export of p53/TP53. MDMX, itself, is essential for the regulation of p53 and binds to p53 in a manner that is similar to its binding to MDM2. Jan 25, 2022 · E3 ubiquitin ligases ensure the precise spatiotemporal control of key molecules during important cellular processes. The RING domain E3 ubiquitin ligase Mdm2 is the master regulator of the tumor suppressor p53. This confusion is due at least in part to studies of p53 degradat … UniProt is the world's leading high-quality, comprehensive and freely accessible resource of protein sequence and functional information. Indeed, several small molecules have been developed and evaluated in various malignancies. Despite the importance of this in regulating the p53 pathway, little is known about the May 31, 2022 · Mouse double minute 2 (MDM2) is an oncogenic E3 ligase that effectively degrades the tumor suppressor p53. How Mdm2 auto-ubiquitination may influence its substrate ubiquitin ligase activity is undefined. Given that the MDM2-p53 forms auto-regulatory loop in which p53 is a substrate o … Aug 24, 2020 · Abstract Background: Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that is over-expressed in many cancers and regulates target proteins through ubiquitination. The E3 ubiquitin ligase MDM2 is a negative regulator of the p53 tumor suppressor protein. Nov 29, 2021 · Our results establish a novel role for MSX1/MSX2 in the transcriptional activation of MDM2 and the resultant increase in MDM2 E3 ligase activity during vascular calcification. However, the regulation of Mdm2 remains not well understood. E3 ubiquitin ligases play an essential role in catalyzing the May 1, 2024 · The large size of the human E3 ligase family suggests that PROTACs can be developed by targeting a large diversity of E3 ligases, some of which have restricted expression patterns with the potential to design disease- or tissue-specific degraders. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. On the other hand … Jul 17, 2025 · E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome (PubMed: 29681526). Like most E3 ligases, Mdm2 can also ubiquitinate itself. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Feb 3, 2006 · Although early studies have suggested that the oncoprotein Mdm2 is the primary E3 ubiquitin ligase for the p53 tumor suppressor, an increasing amount of data suggests that p53 ubiquitination and degradation are more complex than once thought. Here, we briefly review how traditional E3 ligase ligands were discovered, and then outline approaches and ligands that have been recently used to discover new E3 ligases for PROTACs. For the discovery of a first-in-class PROTAC for a target of interest, the E3 ligases commonly hijacked remain the Von Hippel-Lindau (VHL) and Cereblon (CRBN) since potent and accessible ligands are readily available to recruit them. 3. , 2010). Feb 4, 2019 · MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Jan 1, 2025 · Abstract Although an E3 ligase MDM2 is the major negative regulator of the p53 tumor suppressor, a growing body of evidence suggests its p53-independent oncogenic properties. MDM2 and MDM4 form heterodimer polyubiquitin E3 ligases via their RING domain interaction. We will then take an outlook at current and future strategies undertaken that invoke either target-based screening or phenotypic-based approaches, including the use of DNA-encoded libraries (DELs), display May 19, 2022 · Abstract MDM2 and MDM4 are key regulators of p53 and function as oncogenes when aberrantly expressed. Here, we have generated an Mdm2Y487A MDM2 is a major regulator of p53 by acting as a ubiquitin E3 ligase. Beyond regulating p53, MDM2 possesses p53-independent activity in promoting cell cycle progression and tumorigenesis via its RING domain ubiquitin E3 ligase activity. Several lysine residues in p53 C May 19, 2022 · The importance of MDM2 E3-ligase-mediated p53 regulation remains controversial. Feb 17, 2025 · Both mouse double-minute 2 (MDM2), an E3 ubiquitin ligase, and its closely related paralog, MDM4, which lacks E3 activity, play central roles in cellular homeostasis. May 7, 2020 · Hypothesis: We hypothesized that like MDM2-FL, the MDM2-C isoform (lacking exons 5– 9 and containing a full C-terminal RING finger sequence) would maintain E3 ubiquitin ligase activity. Mouse double minute 2 Feb 13, 2025 · The loss of functions of tumor suppressor (TS) genes plays a key role in not only tumor initiation but also tumor progression leading to poor prognosis. . These events occur in a concentration dependent fashion, suggesting that modulating E3 ligase concentration is a cellular regulatory strategy for controlling protein homeostasis and localization. In this process, β-arrestins bind to Mdm2 and recruit it to th May 19, 2022 · MDM2 and MDM4 are key regulators of p53 and function as oncogenes when aberrantly expressed. In the past two decades, many MDM2 inhibitors that disrupt the MDM2-p53 binding have been discovered and developed. , 2008). Materials and Methods: In order to explore the biochemical function of MDM2-C, we used an in vitro ubiquitination assay and a glutaraldehyde cross-linking assay. Jun 1, 2025 · MDM2 is an E3 ligase that targets p53 for degradation, and its overexpression or amplification leads to the loss of p53 function, promoting uncontrolled cell proliferation and contributing to cancer [181], [182]. 5-4 μM. Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase which effectively degrades tumor suppressor p53. Jan 5, 2025 · MDM2 and MDM4 are major negative regulators of tumor suppressor p53. 27 Double minute 2 protein Hdm2 Oncoprotein Mdm2 p53-binding protein Mdm2 RING-type E3 ubiquitin transferase Mdm2 Gene Name MDM2 UniProtKB Entry Q00987 Swiss-Prot Organism Humans NCBI Taxonomy ID 9606 Amino acid sequence >lcl|BSEQ0001997|E3 ubiquitin-protein ligase Mdm2 Jul 5, 2021 · The E3 ligase activity of MDM2 was utilized in the first small-molecule PROTAC by incorporating a molecule belonging to a class of imidazoline derivatives called nutlins, which bind to MDM2 in a nano-to micromolar range (Vassilev et al. Figure 2. For example, the E3 ligase MDM2 ubiquitylates p53 either for degradation (K48 polyubiquitin chain), or for nuclear export (monoubiquitylation). The central acidic domain and C-terminal RING domain of MDM2 are both indispensable for ubiquitination of p53. okwhtixu qji5dt 8efh5 pptnn fq2db7g 43t0i7 gn 8zfke9 khjdfuc 7wjz

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