Article
Medicine, Research & Experimental
Si Chen, Xiang Li, Yinghua Li, Xing Yuan, Chenchen Geng, Songyan Gao, Jinyang Li, Bohan Ma, Zhe Wang, Wuyuan Lu, Hong-Gang Hu
Summary: A stapled peptide-based proteolysis-targeting chimera (SP-PROTAC) was developed, which improved cellular uptake and proteolytic stability while promoting target protein degradation. The optimized SP-PROTAC showed improved binding affinity, helical content, and pharmacokinetic profile compared to its linear counterpart. It effectively killed cancer cells and inhibited tumor progression by promoting the atypical degradation of MDM2 and MDMX and activating p53.
Review
Cell Biology
Alyssa M. Klein, Rafaela Muniz de Queiroz, Divya Venkatesh, Carol Prives
Summary: MDM2 and MDMX, well-known as proteins that restrain the p53 tumor suppressor protein, have diverse functions in cells and are regulated at multiple levels including transcription and protein modification. Both proteins may contribute to oncogenic transformation while also potentially playing a tumor suppressive role in certain contexts. Understanding how various small molecules affecting MDM2 and MDMX may impact their p53-independent activities is crucial due to their therapeutic potential.
GENES & DEVELOPMENT
(2021)
Article
Biochemistry & Molecular Biology
Viktoria K. Ilic, Olga Egorova, Ernest Tsang, Milena Gatto, Yi Wen, Yong Zhao, Yi Sheng
Summary: The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is associated with poor prognosis. MDM2 shows oncogenic activity by negatively regulating tumor suppressor p53 and proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Inhibition of MDM2 activity has been pursued as an attractive direction for anti-cancer therapeutics. This study identified a biflavonoid compound Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment downregulated MDM2 and MDMX and induced apoptosis in various cancer cell lines. Hinokiflavone demonstrated tumor-suppressive activity that is both p53-dependent and -independent.
Article
Biochemistry & Molecular Biology
Yali Wang, Bo Ji, Zhongshui Cheng, Lianghui Zhang, Yingying Cheng, Yingying Li, Jin Ren, Wenbo Liu, Yuanyuan Ma
Summary: A series of novel indolone derivatives were synthesized and evaluated for their binding affinities toward MDM2 and MDMX. Compound A13 showed the most potent affinity and exhibited strong inhibitory effects on multiple cancer cell lines.
Article
Pharmacology & Pharmacy
Xiang Li, Neelakshi Gohain, Si Chen, Yinghua Li, Xiaoyuan Zhao, Bo Li, William D. Tolbert, Wangxiao He, Marzena Pazgier, Honggang Hu, Wuyuan Lu
Summary: The research identified a potent dual-specificity peptide antagonist PMI-M3 of MDM2 and MDMX through systematic mutational analysis and additivity-based molecular design, with ultrahigh affinity and significant antitumor activities both in vitro and in vivo. The peptide inhibitor PMI-M3, occupying the P53-binding pocket of MDM2/MDMX, showed enhanced binding affinity compared to PMI, making it a powerful lead compound for anticancer drug development and aiding molecular design of other P53 activators for cancer therapy.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Oncology
Renier C. Heijkants, Amina F. A. S. Teunisse, Danielle de Jong, Kseniya Glinkina, Hailiang Mei, Szymon M. Kielbasa, Karoly Szuhai, Aart G. Jochemsen
Summary: The tumor suppressor protein p53 is frequently repressed in cancer cells by high levels of MDMX and/or MDM2. This study suggests that the oncogenic functions of MDMX can be partially explained by its regulation of FOXO transcription factors, independent of p53.
Review
Oncology
Murali Munisamy, Nayonika Mukherjee, Levin Thomas, Amy Trinh Pham, Arash Shakeri, Yusheng Zhao, Jill Kolesar, Praveen P. N. Rao, Vivek M. Rangnekar, Mahadev Rao
Summary: Ubiquitination is crucial in regulating p53 stability and function in cancer, particularly through the p53-MDM2-MDMX pathway. Targeting the ubiquitination pathway shows promise as a strategy for precision therapy in cancer treatment.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Chemistry, Medicinal
Hui-juan Luo, Dong-juan Si, Xin-jie Sun, Meng-yun Wang, Yao-bin Yang, Bo Wang, Hong-mei Wen, Wei Li, Jian Liu
Summary: The overexpression of MDM2 and MDMX negatively regulates the function of p53 protein. Disruption of the p53-MDM2/MDMX interaction is a potential strategy for cancer therapy. Through molecular dynamics simulations, alanine scanning, and MM-GBSA calculations, the binding modes of MDM2 and MDMX with their inhibitors are elucidated, and several hot-spot residues are identified. Based on the interaction with hot-spot residues, derivatives with 1,3-diketone and alpha-aminoketone scaffolds are designed and synthesized. Among these compounds, C16 shows the highest binding affinities with MDM2 and MDMX, and exhibits antiproliferative activities, cell migration and invasion inhibition, reactivation of p53 function, cell cycle arrest, and induction of cellular apoptosis in cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Hua Yang, Yanyan Liu, Jingyi Yang, Qing Zhang, Haoran Wang, Yu Chen, Keshu Zhou
Summary: This study revealed the biological roles of deubiquitinase USP25 in the tumorigenesis of DLBCL. USP25 was found to be frequently upregulated in DLBCL and associated with poor prognosis. Inhibition of USP25 suppressed DLBCL growth and migration, while increasing apoptosis. Mechanistically, USP25 stabilized MDM2 and subsequently decreased p53 expression, promoting DLBCL progression.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Hongjin Li, Xiangyan Chen, Minghao Wu, Panpan Song, Xia Zhao
Summary: In recent years, inhibiting the interactions of p53 with MDM2 and MDMX has been recognized as a promising approach for tumor therapy. However, peptide inhibitors face challenges of poor proteolytical stability and low intracellular delivery efficiency. In this study, a bicyclic stapled peptide named p53-16 was designed and synthesized, which showed improved stability and binding affinity for MDM2 and MDMX. Moreover, p53-16 could penetrate cell membranes and selectively inhibit the activity of tumor cells in vitro.
CHINESE CHEMICAL LETTERS
(2022)
Article
Multidisciplinary Sciences
Alyssa M. Klein, Lynn Biderman, David Tong, Bita Alaghebandan, Sakina A. Plumber, Helen S. Mueller, Anne van Vlimmeren, Chen Katz, Carol Prives
Summary: This study suggests that MDM2 and MDMX may play a p53-independent role in maintaining cell-cycle progression by affecting the activity of E2F family members and p73, making them a potential target of interest in cancers lacking wild-type p53.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(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
Oncology
Tao Chen, Fei Wang, Shupei Wei, Yingjie Nie, Xiaotao Zheng, Yu Deng, Xubin Zhu, Yuezhen Deng, Nanshan Zhong, Chengzhi Zhou
Summary: The study revealed that the FGFR/RACK1 complex regulates senescence in LSCC cells by promoting the degradation of p53 through the formation of a complex with MDM2. Inhibition of FGFR or knockdown of RACK1 induced cell senescence, while inhibitors targeting MDM2 and p53 cooperatively inhibited colony formation and metastasis of LSCC cells. This understanding could have important implications for the treatment of LSCC.
CANCER BIOLOGY & MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Jihyun Lee, Jongdoo Kim, Eun Mi Kim, Ukjin Kim, A-Ram Kang, Jong Kuk Park, Hong-Duck Um
Summary: In this study, it was found that p21 acts as a negative regulator of p53 stability, reducing the cellular levels of p53 protein and promoting its degradation. Additionally, p21 promotes the interaction between p53 and Wip1, and forms a trimeric complex with Wip1. The p21/p53 complex is more efficient in facilitating the binding of p53 to Wip1 and Mdm2, suggesting that p21 may be a potential target to restore p53 activity in cancer cells.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Oncology
Rui Shi, Zirong Liu
Summary: RPL15 plays crucial roles in the progression and metastasis of hepatocellular carcinoma (HCC), serving as a promising candidate for targeted therapies.
CANCER CELL INTERNATIONAL
(2022)
Article
Hematology
Jayadev M. Umakanthan, Javeed Iqbal, Connie L. Batlevi, Alyssa Bouska, Lynette M. Smith, Valerie Shostrom, Heather Nutsch, Basem M. William, R. Gregory Bociek, Matthew Lunning, Philip Bierman, Anas Younes, James O. Armitage, Julie M. Vose
BRITISH JOURNAL OF HAEMATOLOGY
(2019)
Article
Hematology
Tayla B. Heavican, Alyssa Bouska, Jiayu Yu, Waseem Lone, Catalina Amador, Qiang Gong, Weiwei Zhang, Yuping Li, Bhavana J. Dave, Maarja-Liisa Nairismagi, Timothy C. Greiner, Julie Vose, Dennis D. Weisenburger, Cynthia Lachel, Chao Wang, Kai Fu, Jadd M. Stevens, Soon Thye Lim, Choon Kiat Ong, Randy D. Gascoyne, Edoardo Missiaglia, Francois Lemonnier, Corinne Haioun, Sylvia Hartmann, Martin Bjerregard Pedersen, Maria Antonella Laginestra, Ryan A. Wilcox, Bin Tean Teh, Noriaki Yoshida, Koichi Ohshima, Masao Seto, Andreas Rosenwald, German Ott, Elias Campo, Lisa M. Rimsza, Elaine S. Jaffe, Rita M. Braziel, Francesco d'Amore, Giorgio Inghirami, Francesco Bertoni, Laurence de Leval, Philippe Gaulard, Louis M. Staudt, Timothy W. McKeithan, Stefano Pileri, Wing C. Chan, Javeed Iqbal
Article
Cell Biology
Neeraj Jain, Keenan Hartert, Saber Tadros, Warren Fiskus, Ondrej Havranek, Man Chun John Ma, Alyssa Bouska, Tayla Heavican, Dhiraj Kumar, Qing Deng, Dalia Moore, Christine Pak, Chih Long Liu, Andrew J. Gentles, Elena Hartmann, Robert Kridel, Karin Ekstrom Smedby, Gunnar Juliusson, Richard Rosenquist, Randy D. Gascoyne, Andreas Rosenwald, Filippo Giancotti, Sattva S. Neelapu, Jason Westin, Julie M. Vose, Matthew A. Lunning, Timothy Greiner, Scott Rodig, Javeed Iqbal, Ash A. Alizadeh, R. Eric Davis, Kapil Bhalla, Michael R. Green
SCIENCE TRANSLATIONAL MEDICINE
(2019)
Article
Public, Environmental & Occupational Health
Baha Abdalhamid, Emily L. Mccutchen, Alyssa C. Bouska, Zhang Weiwei, Brianna Loeck, Steven H. Hinrichs, Peter C. Iwen
JOURNAL OF INFECTION AND PUBLIC HEALTH
(2019)
Article
Hematology
Catalina Amador, Timothy C. Greiner, Tayla B. Heavican, Lynette M. Smith, Karen Tatiana Galvis, Waseem Lone, Alyssa Bouska, Francesco D'Amore, Martin Bjerregaard Pedersen, Stefano Pileri, Claudio Agostinelli, Andrew L. Feldman, Andreas Rosenwald, German Ott, Anja Mottok, Kerry J. Savage, Laurence de Leval, Philippe Gaulard, Soon Thye Lim, Choon Kiat Ong, Sarah L. Ondrejka, Joo Song, Elias Campo, Elaine S. Jaffe, Louis M. Staudt, Lisa M. Rimsza, Julie Vose, Dennis D. Weisenburger, Wing C. Chan, Javeed Iqbal
Letter
Oncology
Joo Y. Song, Caoimhe Egan, Alyssa C. Bouska, Weiwei Zhang, Qiang Gong, Girish Venkataraman, Alex F. Herrera, Lu Chen, Rebecca Ottesen, Joyce C. Niland, Victoria Bedell, Maria Valle-Catuna, Joyce Murata-Collins, Dennis D. Weisenburger, Javeed Iqbal, Elaine S. Jaffe, Wing C. Chan
Article
Oncology
Jacob E. Robinson, Timothy C. Greiner, Alyssa C. Bouska, Javeed Iqbal, Christine E. Cutucache
FRONTIERS IN ONCOLOGY
(2020)
Article
Hematology
Gehong Dong, Yuping Li, Logan Lee, Xuxiang Liu, Yunfei Shi, Xiaoqian Liu, Alyssa Bouska, Qiang Gong, Lingbo Kong, Jinhui Wang, Chih-Hong Lou, Timothy W. McKeithan, Javeed Iqbal, Wing C. Chan
Summary: The study utilized two different CRISPR/Cas9 approaches to generate PRDM1-/- primary NK cells to investigate the role of PRDM1 in NK cell homeostasis. Results showed that PRDM1(-/-) NK cells exhibited higher proliferation rate and lower apoptosis compared to wild-type cells, with gene expression profiling revealing enrichment in pathways associated with proliferation and cell cycle.
Article
Hematology
Kota Fukumoto, Mamiko Sakata-Yanagimoto, Manabu Fujisawa, Tatsuhiro Sakamoto, Hiroaki Miyoshi, Yasuhito Suehara, Tran Bich Nguyen, Sakurako Suma, Shintaro Yanagimoto, Yuichi Shiraishi, Kenichi Chiba, Alyssa Bouska, Keisuke Kataoka, Seishi Ogawa, Javeed Iqbal, Kouichi Ohshima, Shigeru Chiba
Letter
Hematology
Cheng Wang, Pamela A. Althof, Chengfeng Bi, Weiwei Zhang, Alyssa C. Bouska, Tian Tian, Xuan Zhang, Nanxi Jiang, Guohua Yu, Hongxia Cheng, Javeed Iqbal, Julie M. Vose, Jennifer N. Sanmann, Kai Fu
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Hematology
Man Chun John Ma, Saber Tadros, Alyssa Bouska, Tayla Heavican, Haopeng Yang, Qing Deng, Dalia Moore, Ariz Akhter, Keenan Hartert, Neeraj Jain, Jordan Showell, Sreejoyee Ghosh, Lesley Street, Marta Davidson, Christopher Carey, Joshua Tobin, Deepak Perumal, Julie M. Vose, Matthew A. Lunning, Aliyah R. Sohani, Benjamin J. Chen, Shannon Buckley, Loretta J. Nastoupil, R. Eric Davis, Jason R. Westin, Nathan H. Fowler, Samir Parekh, Maher Gandhi, Sattva Neelapu, Douglas Stewart, Kapil Bhalla, Javeed Iqbal, Timothy Greiner, Scott J. Rodig, Adnan Mansoor, Michael R. Green
Summary: This study comprehensively analyzed the genomic landscapes of multiple B-cell non-Hodgkin lymphoma (B-NHL) subtypes, and identified common features and subtype-specific patterns of genetic alterations. The study also revealed potential patterns of genetic cooperation that contribute to lymphomagenesis, providing important insights into the pathogenesis of B-NHL.
Article
Hematology
Jennifer R. Chapman, Alyssa C. Bouska, Weiwei Zhang, Juan Pablo Alderuccio, Izidore S. Lossos, Lisa M. Rimsza, Alanna Maguire, Shuhua Yi, Wing C. Chan, Francisco Vega, Joo Y. Song
Summary: In the era of cART, approximately half of HIV-DLBCL are EBV-related. HIV-DLBCL are enriched for MYC rearrangements and mutations, and lack BCL2 rearrangements regardless of EBV status. EBV-negative and EBV-positive HIV-DLBCL show important genetic and clinical differences, with the former having more mutations and higher mutation frequency for genes like TP53, SGK1, and EP300, while the latter occur in lower CD4 count, non-GCB origin, and recurrent STAT3 mutations.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Oncology
Waseem Lone, Alyssa Bouska, Sunandini Sharma, Catalina Amador, Mallick Saumyaranjan, Tyler A. Herek, Tayla B. Heavican, Jiayu Yu, Soon Thye Lim, Choon Kiat Ong, Graham W. Slack, Kerry J. Savage, Andreas Rosenwald, German Ott, James R. Cook, Andrew L. Feldman, Lisa M. Rimsza, Timothy W. McKeithan, Timothy C. Greiner, Dennis D. Weisenburger, Federica Melle, Giovanna Motta, Stefano Pileri, Julie M. Vose, Wing C. Chan, Javeed Iqbal
Summary: This study revealed differences in miRNA expression and signaling pathways among different subtypes of T-cell lymphoma, identifying certain miRNAs and possible regulatory mechanisms associated with disease occurrence and progression.
CLINICAL CANCER RESEARCH
(2021)
Article
Medicine, Research & Experimental
Sylvain Carras, Dimitri Chartoire, Sylvain Mareschal, Mael Heiblig, Antoine Marcais, Remy Robinot, Mirjam Urb, Roxane M. Pommier, Edith Julia, Amel Chebel, Aurelie Verney, Charlotte Bertheau, Emilie Bardel, Caroline Fezelot, Lucien Courtois, Camille Lours, Alyssa Bouska, Sunandini Sharma, Christine Lefebvre, Jean-Pierre Rouault, David Sibon, Anthony Ferrari, Javeed Iqbal, Laurence de Leval, Philippe Gaulard, Alexandra Traverse-Glehen, Pierre Sujobert, Mathieu Blery, Gilles Salles, Thierry Walzer, Emmanuel Bachy, Laurent Genestier
Summary: Chronic TCR stimulation may drive T cell lymphomagenesis, but does not affect PTCL cell survival. NK cell-like reprogramming may occur in PTCL cells, with expression of NK receptors and downstream signaling molecules.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Hematology
Alyssa Bouska, Chengfeng Bi, Waseem Lone, Weiwei Zhang, Ambreen Kedwaii, Tayla Heavican, Cynthia M. Lachel, Jiayu Yu, Roberto Ferro, Nanees Eldorghamy, Timothy C. Greiner, Julie Vose, Dennis D. Weisenburger, Randy D. Gascoyne, Andreas Rosenwald, German Ott, Elias Campo, Lisa M. Rimsza, Elaine S. Jaffe, Rita M. Braziel, Reiner Siebert, Rodney R. Miles, Sandeep Dave, Anupama Reddy, Jan Delabie, Louis M. Staudt, Joo Y. Song, Timothy W. McKeithan, Kai Fu, Michael Green, Wing C. Chan, Javeed Iqbal