Targeting MDM2 for novel molecular therapy: Beyond oncology

Wang, Wei; Qin, Jiang‐Jiang; Rajaei, Mehrdad; Li, Xin; Yu, Xiaoyi; Hunt, Courtney; Zhang, Ruiwen

doi:10.1002/med.21637

Cited by 64 publications

(57 citation statements)

References 139 publications

(304 reference statements)

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“…The MDM2/MDMX-p53 circuitry plays a pivotal role in cancer cell proliferation, cell cycle progression, apoptosis, and senescence (Karni-Schmidt et al, 2016;Wang et al, 2019b), while USP7 is a critical regulator of this circuitry and tightly controls the stabilities of these proteins, thereby contributing to cancer initiation, progression, and metastasis (Bhattacharya et al, 2018;Rawat et al, 2019). Many MDM2/MDMX inhibitors have been developed for cancer therapy Wang et al, 2018aWang et al, ,b, 2019bde Oliveira Ribeiro et al, 2020), and some of them are in clinical trials (Liu et al, 2019b;Rafal et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The oncoproteins MDM2 and MDMX are not only the major negative regulators of p53 but also the well-characterized substrates of USP7 (Sarkari et al, 2010;Nag et al, 2013;Karni-Schmidt et al, 2016;Wang et al, 2019b). MDM2 and MDMX include 491 and 490 amino acid residues, respectively and share a great structural similarity (Nag et al, 2013;Karni-Schmidt et al, 2016).…”

Section: The Usp7-mdm2/mdmx-p53 Networkmentioning

confidence: 99%

“…The p53 tumor suppressor plays a critical role in protecting normal cells from transformation and tumorigenesis through transactivation of the genes related to cell growth arrest, apoptosis, and senescence (Nag et al, 2013;Liu et al, 2019a). The MDM2 and MDMX oncogenes have been demonstrated to promote tumor growth and metastasis via both p53-dependent and p53-independent mechanisms (Karni-Schmidt et al, 2016;Wang et al, 2019b). The overexpression and amplification of MDM2 and MDMX and the loss-of-function mutation of p53 are the common and crucial events in the initiation, progression, and metastasis of human cancers, which have been comprehensively discussed recently (Walerych et al, 2015;Hou et al, 2019).…”

Section: The Role Of Usp7-mdm2/mdmx-p53 Network In Human Cancer and Imentioning

confidence: 99%

“…HBX 19,818 has further been shown to inhibit cell proliferation and induce G1 arrest and apoptosis in HCT116 cells. It has also been found that HBX 19,818 inhibits cancer cell viability in a p53-independent manner, which emphasizes the critical role of the p53-independent functions of MDM2 and MDMX in cancer cells (Qin et al, 2018;Wang et al, 2019b). However, both HBX 19,818 and HBX 28,258 have not been evaluated in any animal models, and further investigation for their in vivo efficacy and safety should be performed.…”

Section: Inhibiting Usp7 Activity Via Covalent Bindingmentioning

confidence: 99%

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Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitinproteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: The Usp7-mdm2/mdmx-p53 Networkmentioning

confidence: 99%

Section: The Role Of Usp7-mdm2/mdmx-p53 Network In Human Cancer and Imentioning

confidence: 99%

Section: Inhibiting Usp7 Activity Via Covalent Bindingmentioning

confidence: 99%

See 2 more Smart Citations

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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“…131,159,176 A similar situation occurs with Mdm2, which can promote both the K48 linkage ubiquitination and the neddylation of p53. 219,483 To understand the dynamics and complexity of such events, it will be necessary to place special emphasis on dissecting the diverse mechanisms of Ub chain assembly by E3s.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

424

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Genotoxic stress response: What is the role of cytoplasmic mRNA fate?

2021

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Genotoxic stress leads to DNA damage which can be detrimental to the cell. A wellorchestrated cellular response is mounted to manage and repair the genotoxic stressinduced DNA damage. Our understanding of genotoxic stress response is derived mainly from studies focused on transcription, mRNA splicing, and protein turnover. Surprisingly not as much is understood about the role of mRNA translation and decay in genotoxic stress response. This is despite the fact that regulation of gene expression at the level of mRNA translation and decay plays a critical role in a myriad of cellular processes. This review aims to summarize some of the known findings of the role of mRNA translation and decay by focusing on two categories of examples. We discuss examples of mRNA whose fates are regulated in the cytoplasm and RNA-binding proteins that regulate mRNA fates in response to genotoxic stress.

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Targeting MDM2 for novel molecular therapy: Beyond oncology

Cited by 64 publications

References 139 publications

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

The role of ubiquitination in tumorigenesis and targeted drug discovery

Genotoxic stress response: What is the role of cytoplasmic mRNA fate?

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