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The 10th International MDM2 Workshop—Opening Up New Avenues for MDM2...
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The 10th International MDM2 Workshop—Opening Up New Avenues for MDM2 and p53 Research

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 4534

Special Issue Editors

Dr. Manabu Kurokawa

E-Mail Website
Guest Editor
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
Interests: cancer; p53; ubiquitin ligase; lipid metabolism
Dr. Tomoo Iwakuma

E-Mail Website
Guest Editor
Department of Pediatrics, Children's Mercy Research Institute, Kansas City, MO 64108, USA
Interests: p53; mutant p53; MDM2; drug discovery; osteosarcoma; Ewing sarcoma
Dr. Koji Itahana

E-Mail Website
Guest Editor
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
Interests: develop novel therapeutic strategies against cancer by investigating ARF-MDM2-p53 tumor suppressive mechanisms and cancer metabolism
Dr. Rieko Ohki

E-Mail Website1 Website2
Guest Editor
Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
Interests: p53; cancer; tumor biology; neuoendocrine tumor; PHLDA3; IER5
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of Cancers will focus on the E3 ubiquitin ligase MDM2 in a special collaboration with the 10th International MDM2 Workshop (https://www.10thmdm2.jp), taking place in Tokyo, Japan, on 15–18 October 2023.

MDM2 (Murine Double Minute 2) is a RING-domain-containing E3 ubiquitin ligase and is the most critical negative regulator of p53. It was first discovered in 1987 as a gene product amplified in spontaneously transformed mouse 3T3-DM cells, and human MDM2 was later cloned in 1992. At the molecular level, MDM2 functions as a dimer, most notably coordinating with its homolog MDM4 (MDMX) to inhibit p53. Since its initial discovery, numerous studies have been conducted to elucidate its oncogenic functions. For example, MDM2 is often overexpressed or amplified in several cancer types, and its overexpression could cause cancer in mice. Accordingly, much effort has been spent on developing clinical inhibitors of the MDM2/MDM4-p53 interaction. While the inhibition of p53 is often considered its most prominent role, accumulating evidence indicates that MDM2 also has p53-independent functions. Given its critical and diverse roles in cancer development, this Special Issue will highlight both clinical and basic research investigating MDM2.

Although this Special Issue collaborates with the 10th International MDM2 Workshop, all relevant manuscripts are welcome, including research and review articles.

Dr. Manabu Kurokawa
Dr. Tomoo Iwakuma
Dr. Koji Itahana
Dr. Rieko Ohki
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (4 papers)

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Research

14 pages, 6976 KiB  
Article
Long Noncoding RNA RP11-278A23.1, a Potential Modulator of p53 Tumor Suppression, Contributes to Colorectal Cancer Progression
by Masayo Kamikokura, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino and Masashi Idogawa
Cancers 2024, 16(5), 882; https://doi.org/10.3390/cancers16050882 - 22 Feb 2024
Viewed by 664
Abstract
Recently, many studies revealed that long noncoding RNAs (lncRNAs) play important roles in cancers. To identify lncRNAs contributing to colorectal cancers, we screened lncRNAs through expression and survival analyses in datasets from The Cancer Genome Atlas (TCGA). The screen revealed that RP11-278A23.1 expression [...] Read more.
Recently, many studies revealed that long noncoding RNAs (lncRNAs) play important roles in cancers. To identify lncRNAs contributing to colorectal cancers, we screened lncRNAs through expression and survival analyses in datasets from The Cancer Genome Atlas (TCGA). The screen revealed that RP11-278A23.1 expression is significantly increased in colorectal cancer tissues compared with normal tissues and that high RP11-278A23.1 expression correlates with poor prognosis. The knockdown of RP11-278A23.1 inhibited the growth of and promoted apoptosis in colorectal cancer cells. Next, to comprehensively examine differentially expressed genes after RP11-278A23.1 knockdown, RNA sequencing was performed in HCT116 cells. The expression of p21, a p53 target gene, was significantly upregulated, and the expression of several p53 target proapoptotic genes was also altered. RP11-278A23.1 knockdown increased p53 expression at the translational level but not at the transcriptional level. Interestingly, RP11-278A23.1 knockdown also altered the expression of these proapoptotic genes in DLD1 cells with mutated p53 and in p53-knockout HCT116 cells. These results suggest that RP11-278A23.1 modifies the expression of these apoptosis-related genes in p53-dependent and p53-independent manners. In summary, lncRNA RP11-278A23.1 contributes to colorectal cancer progression by promoting cell growth and inhibiting apoptosis, suggesting that this lncRNA may be a useful therapeutic target. Full article
(This article belongs to the Special Issue The 10th International MDM2 Workshop—Opening Up New Avenues for MDM2 and p53 Research)
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13 pages, 4698 KiB  
Article
Ninjurin 2, a Cell Adhesion Molecule and a Target of p53, Modulates Wild-Type p53 in Growth Suppression and Mutant p53 in Growth Promotion
by Jin Zhang, Xiangmudong Kong, Hee Jung Yang, Shakur Mohibi, Christopher August Lucchesi, Weici Zhang and Xinbin Chen
Cancers 2024, 16(1), 229; https://doi.org/10.3390/cancers16010229 - 04 Jan 2024
Cited by 1 | Viewed by 1114
Abstract
The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. [...] Read more.
The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. However, the biology of NINJ2 has not been well-explored. By using multiple in vitro cell lines and genetically engineered mouse embryo fibroblasts (MEFs), we showed that NINJ2 is induced by DNA damage in a p53-dependent manner. Moreover, we found that the loss of NINJ2 promotes p53 expression via mRNA translation and leads to growth suppression in wild-type p53-expressing MCF7 and Molt4 cells and premature senescence in MEFs in a wild-type p53-dependent manner. Interestingly, NINJ2 also regulates mutant p53 expression, and the loss of NINJ2 promotes cell growth and migration in mutant p53-expressing MIA-PaCa2 cells. Together, these data indicate that the mutual regulation between NINJ2 and p53 represents a negative feedback loop, and the NINJ2-p53 loop has opposing functions in wild-type p53-dependent growth suppression and mutant p53-dependent growth promotion. Full article
(This article belongs to the Special Issue The 10th International MDM2 Workshop—Opening Up New Avenues for MDM2 and p53 Research)
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11 pages, 2723 KiB  
Article
Characterization of an Mtbp Hypomorphic Allele in a Diethylnitrosamine-Induced Liver Carcinogenesis Model
by Atul Ranjan, Elizabeth A. Thoenen, Atsushi Kaida, Stephanie Wood, Terry Van Dyke and Tomoo Iwakuma
Cancers 2023, 15(18), 4596; https://doi.org/10.3390/cancers15184596 - 16 Sep 2023
Viewed by 810
Abstract
MTBP is implicated in cell cycle progression, DNA replication, and cancer metastasis. However, the function of MTBP remains enigmatic and is dependent on cellular contexts and its cellular localization. To understand the in vivo physiological role of MTBP, it is important to generate [...] Read more.
MTBP is implicated in cell cycle progression, DNA replication, and cancer metastasis. However, the function of MTBP remains enigmatic and is dependent on cellular contexts and its cellular localization. To understand the in vivo physiological role of MTBP, it is important to generate Mtbp knockout mice. However, complete deletion of the Mtbp gene in mice results in early embryonic lethality, while its heterozygous deletion shows modest biological phenotypes, including enhanced cancer metastasis. To overcome this and better characterize the in vivo physiological function of MTBP, we, for the first time, generated mice that carry an Mtbp hypomorphic allele (MtbpH) in which Mtbp protein is expressed at approximately 30% of that in the wild-type allele. We treated wild-type, Mtbp+/−, and MtbpH/− mice with a liver carcinogen, diethylnitrosamine (DEN), and found that the MtbpH/− mice showed worse overall survival when compared to the wild-type mice. Consistent with previous reports using human liver cancer cells, mouse embryonic fibroblasts (MEFs) from the MtbpH/− mice showed an increase in the nuclear localization of p-Erk1/2 and migratory potential. Thus, MtbpH/− mice and cells from MtbpH/− mice are valuable to understand the in vivo physiological role of Mtbp and validate the diverse functions of MTBP that have been observed in human cells. Full article
(This article belongs to the Special Issue The 10th International MDM2 Workshop—Opening Up New Avenues for MDM2 and p53 Research)
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11 pages, 3134 KiB  
Article
Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells
by Yuta Mitobe, Shuhei Suzuki, Yurika Nakagawa-Saito, Keita Togashi, Asuka Sugai, Yukihiko Sonoda, Chifumi Kitanaka and Masashi Okada
Cancers 2023, 15(17), 4326; https://doi.org/10.3390/cancers15174326 - 30 Aug 2023
Cited by 3 | Viewed by 1351
Abstract
The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study [...] Read more.
The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 on inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2–p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2′s interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells. Full article
(This article belongs to the Special Issue The 10th International MDM2 Workshop—Opening Up New Avenues for MDM2 and p53 Research)
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