Article
Biochemistry & Molecular Biology
Kester Mo Henningsen, Valentina Manzini, Anna Magerhans, Sabrina Gerber, Matthias Dobbelstein
Summary: MDM2 can remove p53 from promoters by rapidly terminating its interactions with chromatin in a ubiquitin-dependent manner, in addition to its antagonism through covering the transactivation domain and destabilization.
Review
Biochemistry & Molecular Biology
Lucia Haronikova, Ondrej Bonczek, Pavlina Zatloukalova, Filip Kokas-Zavadil, Martina Kucerikova, Philip J. Coates, Robin Fahraeus, Borivoj Vojtesek
Summary: This review discusses the mechanism of action, determinants of sensitivity, and resistance issues of MDM2 inhibitors, emphasizing the need for patient stratification based on these aspects to achieve better clinical responses.
CELLULAR & MOLECULAR BIOLOGY LETTERS
(2021)
Review
Biochemistry & Molecular Biology
Neha Bhatia, Rakesh Khator, Swanand Kulkarni, Yogesh Singh, Pradeep Kumar, Suresh Thareja
Summary: The discovery of MDM2 and MDM2-p53 interaction inhibitors has revolutionized anticancer research due to their involvement in about 50% of cancer cases globally. In addition to inhibiting MDM2, targeting the interaction between MDM2 and p53 has proven to be an effective strategy for anticancer drug development. Both natural and synthetic molecules have shown promising MDM2 inhibitory potential. This review focuses on the pathophysiology of the MDM2-p53 interaction loop, characteristics of the active site, and the efficacy of various inhibitors from recent patents.
CURRENT MEDICINAL CHEMISTRY
(2023)
Review
Medicine, General & Internal
Giorgio Zauli, Sara AlHilali, Samar Al-Swailem, Paola Secchiero, Rebecca Voltan
Summary: This review summarizes the ocular manifestations and transmission of SARS-CoV-2 infection, and suggests the potential use of small molecule non-genotoxic inhibitors to protect the eyes from infection.
FRONTIERS IN MEDICINE
(2022)
Review
Oncology
Arianna Romani, Enrico Zauli, Giorgio Zauli, Saleh AlMesfer, Samar Al-Swailem, Rebecca Voltan
Summary: MDM2 is the main inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The short half-life of p53 in normal cells and tissues may have potential harmful effects if its levels increase uncontrollably. While p53 mutations are rare in retinoblastoma, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. This minireview discusses the potential use of nutlin-3, a prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for treating retinoblastoma. The review also explores the relative contribution of p53-mediated gene transcription and mitochondrial perturbation to retinoblastoma treatment.
FRONTIERS IN ONCOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Wen-fang Li, Leader Alfason, Can Huang, Yu Tang, Li Qiu, Makoto Miyagishi, Shou-rong Wu, Vivi Kasim
Summary: This study reveals that p52-ZER6 may be a potential biomarker for determining patients appropriate for MDM2-p53 binding inhibition-based antitumor therapy, and demonstrates the potential of combinatorial therapy using MDM2-p53 binding inhibitors and p52-ZER6 inhibition.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Environmental Sciences
Jinyao Yin, Qian Zhou, Jingwen Tan, Wangjun Che, Yuefeng He
Summary: Arsenic, a human carcinogen, poses a threat to global environmental health. This study investigated the effect of arsenic on MDM2, p53, and their phosphorylation. The findings suggest that arsenic and its methylated metabolites can modulate the expression and phosphorylation of MDM2 and p53, as well as the interaction between MDM2 and p53.
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
(2022)
Article
Oncology
Konstantina Psatha, Laxmikanth Kollipara, Elias Drakos, Elena Deligianni, Konstantinos Brintakis, Eustratios Patsouris, Albert Sickmann, George Z. Rassidakis, Michalis Aivaliotis
Summary: The activation of wild-type p53 protein in human lymphoma is a promising therapeutic strategy. An in vitro integrative comparative multi-omics analysis of different lymphoma types before and after p53 activation can shed light on the molecular mechanisms involved. Our findings provide valuable insights into the role of specific proteins and pathways in lymphoma pathogenesis and the global effect of nutlin-3a, which can guide targeted studies on lymphoma progression and resistance.
Article
Biochemistry & Molecular Biology
Tatyana Grigoreva, Aleksandra Sagaidak, Angelina Romanova, Daria Novikova, Aleksander Garabadzhiu, Viacheslav Tribulovich
Summary: The development of chemoresistance in colorectal cancer cells was replicated in vitro by gradually increasing the drug content in the medium, resulting in reduced sensitivity to drugs of different mechanisms of action in resistant cell lines. The cells were found to utilize a universal efflux defense mechanism, which could be partially neutralized by inhibitors of ABC transport proteins, such as P-glycoprotein, confirming its role in chemoresistance.
CHEMICO-BIOLOGICAL INTERACTIONS
(2021)
Article
Biochemistry & Molecular Biology
Sibasish Mohanty, Pallavi Mohapatra, Omprakash Shriwas, Shamima Azma Ansari, Manashi Priyadarshini, Swatismita Priyadarsini, Rachna Rath, Mahesh Sultania, Saroj Kumar Das Majumdar, Rajeeb K. Swain, Rupesh Dash
Summary: This study identified MINK1 as a key mediator of 5FU resistance in OSCC by modulating the p53 signaling pathway. The inhibitor of MINK1 kinase activity, Lestaurtinib, can restore sensitivity to 5FU and reduce tumor burden, suggesting a potential new treatment strategy for advanced OSCC.
Article
Pharmacology & Pharmacy
Giada Lodi, Valentina Gentili, Fabio Casciano, Arianna Romani, Giorgio Zauli, Paola Secchiero, Enrico Zauli, Carolina Simioni, Silvia Beltrami, Mercedes Fernandez, Roberta Rizzo, Rebecca Voltan
Summary: SARS-CoV viruses downregulate antiviral defenses by manipulating p53, a key molecule for cell homeostasis and immune control. Using MDM2 inhibitors to raise p53 levels can inhibit cell cycle and virus release, as well as reduce the expression of inflammatory cytokines. Therefore, p53 and MDM2 inhibitors may be potential therapies against SARS-CoV-2.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Wei-Lun Chang, Chih-Hsiung Hsieh, I-Ying Kuo, Chien-Hsun Lin, Yu-Lin Huang, Yi-Ching Wang
Summary: A novel therapeutic agent, Nutlin-3, has been proposed to enhance the treatment efficacy of chemoradiation-resistant ESCC by regulating the expression of transcription factor proteins p53 and RB and downregulating the level of DNA methyltransferase. It has the potential for clinical application.
MOLECULAR CARCINOGENESIS
(2022)
Article
Oncology
Irene Veneziani, Paola Infante, Elisa Ferretti, Ombretta Melaiu, Cecilia Battistelli, Valeria Lucarini, Mirco Compagnone, Carmine Nicoletti, Aurora Castellano, Stefania Petrini, Marzia Ognibene, Annalisa Pezzolo, Lucia Di Marcotullio, Roberto Bei, Lorenzo Moretta, Vito Pistoia, Doriana Fruci, Vincenzo Barnaba, Franco Locatelli, Loredana Cifaldi
Summary: The study demonstrated that Nutlin-3a could enhance NK cell-mediated killing of neuroblastoma cells by restoring p53 function and increasing ligand expression for NK-ARs. Adoptive transfer of human NK cells into neuroblastoma-bearing mice resulted in tumor shrinkage and improved overall survival. Nutlin-3a also boosted NK cell-mediated cytotoxicity against neuroblastoma spheroids by increasing ligand expression in primary neuroblastoma cells.
CANCER IMMUNOLOGY RESEARCH
(2021)
Article
Multidisciplinary Sciences
Jing Zhao, Alan Blayney, Xiaorong Liu, Lauren Gandy, Weihua Jin, Lufeng Yan, Jeung-Hoi Ha, Ashley J. Canning, Michael Connelly, Chao Yang, Xinyue Liu, Yuanyuan Xiao, Michael S. Cosgrove, Sozanne R. Solmaz, Yingkai Zhang, David Ban, Jianhan Chen, Stewart N. Loh, Chunyu Wang
Summary: Epigallocatechin gallate (EGCG) in green tea induces apoptosis in cancerous cells through a direct interaction with the tumor suppressor p53, inhibiting p53 ubiquitination by its regulatory E3 ligase MDM2 and stabilizing p53 for anti-tumor activity.
NATURE COMMUNICATIONS
(2021)
Article
Medicine, General & Internal
Sahar Javadi, Yue Li, Jie Sheng, Lucy Zhao, Yao Fu, Daifeng Wang, Xinyu Zhao
Summary: Transient Nutlin-3 treatment can prevent neurogenesis and cognitive deficits in mature adult FXS mice, potentially through modulating the adult neurogenic niche.
Article
Biochemistry & Molecular Biology
Meng Yuan, Iain W. McNae, Yiyuan Chen, Elizabeth A. Blackburn, Martin A. Wear, Paul A. M. Michels, Linda A. Fothergill-Gilmore, Ted Hupp, Malcolm D. Walkinshaw
BIOCHEMICAL JOURNAL
(2018)
Article
Chemistry, Physical
Mert Gur, Elizabeth A. Blackburn, Jia Ning, Vikram Narayan, Kathryn L. Ball, Malcolm D. Walkinshaw, Burak Erman
JOURNAL OF CHEMICAL PHYSICS
(2018)
Article
Biochemistry & Molecular Biology
Alice Rose Mitchell, Meng Yuan, Hugh P. Morgan, Iain W. McNae, Elizabeth A. Blackburn, Thierry Le Bihan, Rafael A. Homem, Manda Yu, Gary J. Loake, Paul A. Michels, Martin A. Wear, Malcolm D. Walkinshaw
BIOCHEMICAL JOURNAL
(2018)
Article
Biochemistry & Molecular Biology
Peter M. Fernandes, James Kinkead, Iain W. McNae, Frederic Bringaud, Paul A. M. Michels, Malcolm D. Walkinshaw
BIOCHEMICAL JOURNAL
(2019)
Article
Biochemistry & Molecular Biology
Peter M. Fernandes, James Kinkead, Iain W. McNae, Monserrat Vasquez-Valdivieso, Martin A. Wear, Paul A. M. Michels, Malcolm D. Walkinshaw
Article
Cell Biology
Thibault Legal, Daniel Hayward, Agata Gluszek-Kustusz, Elizabeth A. Blackburn, Christos Spanos, Juri Rappsilber, Ulrike Gruneberg, Julie P. I. Welburn
JOURNAL OF CELL SCIENCE
(2020)
Article
Biochemistry & Molecular Biology
Assel Baibek, Muhammed Ucuncu, Elizabeth A. Blackburn, Mark Bradley, Annamaria Lilienkampf
Summary: Peptides with pan-antimicrobial affinity were synthesized and decorated with environmentally sensitive fluorophores, which showed efficient labeling against a range of clinically relevant fungal and bacterial species. The study indicated that probes containing exclusively l or d-amino acids were able to rapidly and effectively label all microbial species, highlighting the importance of the alpha-helical peptide structure for interaction with the microbial cell membrane.
Article
Biochemistry & Molecular Biology
Peter M. Fernandes, James Kinkead, Iain McNae, Paul A. M. Michels, Malcolm D. Walkinshaw
BIOCHEMICAL JOURNAL
(2020)
Article
Multidisciplinary Sciences
Iain W. McNae, James Kinkead, Divya Malik, Li-Hsuan Yen, Martin K. Walker, Chris Swain, Scott P. Webster, Nick Gray, Peter M. Fernandes, Elmarie Myburgh, Elizabeth A. Blackburn, Ryan Ritchie, Carol Austin, Martin A. Wear, Adrian J. Highton, Andrew J. Keats, Antonio Vong, Jacqueline Dornan, Jeremy C. Mottram, Paul A. M. Michels, Simon Pettit, Malcolm D. Walkinshaw
Summary: The parasitic protist Trypanosoma brucei relies on glycolysis for ATP production and has challenging drug targets due to the highly conserved active sites of glycolytic enzymes. Novel allosteric inhibitors of trypanosome phosphofructokinase have been developed to block glycolysis, showing rapid parasite kill times in a murine model of Human African Trypanosomiasis. The study demonstrates the possibility of targeting glycolysis with species-specific inhibitors to tackle various proliferative or infectious diseases.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Andrew G. Bease, Elizabeth A. Blackburn, Cosmin Chintoan-Uta, Shaun Webb, Robin L. Cassady-Cain, Mark P. Stevens
Summary: Lymphostatin (LifA) is a protein expressed by attaching & effacing Escherichia coli, playing a crucial role in intestinal colonization. It inhibits lymphocyte proliferation and synthesis of proinflammatory cytokines. The C1480A mutation significantly impairs lymphostatin activity against T cells.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Cell Biology
Maria Alba Abad, Tanmay Gupta, Michael A. Hadders, Amanda Meppelink, J. Pepijn Wopken, Elizabeth Blackburn, Juan Zou, Anjitha Gireesh, Lana Buzuk, David A. Kelly, Toni McHugh, Juri Rappsilber, Susanne M. A. Lens, A. Arockia Jeyaprakash
Summary: It has been discovered that the interaction between Sgo1 and Survivin is crucial for the assembly of CPC-Sgo1 complex. Disrupting the binding between Sgo1 and Survivin disrupts the assembly of CPC-Sgo1 and affects the localization and function of CPC at the centromere. Sgo1 and H3T3ph both interact with the same surface on Survivin to bind CPC.
JOURNAL OF CELL BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Jordi Juarez-Jimenez, Arun A. Gupta, Gogulan Karunanithy, Antonia S. J. S. Mey, Charis Georgiou, Harris Ioannidis, Alessio De Simone, Paul N. Barlow, Alison N. Hulme, Malcolm D. Walkinshaw, Andrew J. Baldwin, Julien Michel
Article
Chemistry, Multidisciplinary
Pattama Wapeesittipan, Antonia S. J. S. Mey, Malcolm D. Walkinshaw, Julien Michel
COMMUNICATIONS CHEMISTRY
(2019)
Article
Chemistry, Multidisciplinary
Alessio De Simone, Charis Georgiou, Harris Ioannidis, Arun A. Gupta, Jordi Juarez-Jimenez, Dahlia Doughty-Shenton, Elizabeth A. Blackburn, Martin A. Wear, Jonathan P. Richards, Paul N. Barlow, Neil Carragher, Malcolm D. Walkinshaw, Alison N. Hulme, Julien Michel
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)