Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4.
TL;DR: This work presents a novel and scalable approach to gene expression engineering that allows for real-time annotation of gene expression changes in response to cancerigenicity and shows promise in finding novel and efficient treatments for cancer.
Abstract: 1 Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), University of Ghent, Technologiepark, 927, Ghent B9052, Belgium 2 Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, CA 92037, USA 3 Gene Expression and Diseases Unit, Institut Pasteur, Paris, France 4 The University of Texas Graduate School of Biomedical Sciences and department of Molecular Genetics, Section of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA * Corresponding author: J-C Marine, Laboratory For Molecular Cancer Biology, VIB, Technologiepark, 927, Ghent B-9052, Belgium. Tel: þ 32-93-313-640; Fax: þ 32-93-313-516; E-mail: chris.marine@dmbr.ugent.be
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TL;DR: It is suggested that, in addition to the 12q13–15 amplification, NF1 inactivation mutation and other CNAs may contribute to DDLPS tumorigenesis accompanied by aggressive clinical features.
Abstract: Dedifferentiated liposarcoma (DDLPS), which accounts for an estimated 15–20% of liposarcomas, is a high-grade and aggressive malignant neoplasm, exhibiting a poor response to available therapeutic agents. However, genetic alteration profiles of DDLPS as well as the role of NF1 mutations have not been studied extensively. The current study reports a patient presenting with rapidly growing DDLPS accompanied by multiple lung and pleural metastases, in whom whole-exome sequencing revealed a NF1 truncating mutation of the known pathogenic variant, c.C7486T, p.R2496X, as well as multiple copy number alterations (CNAs), including the well-known 12q13–15 amplification, and multiple chromothripsis events encompassing potential cancer-related genes. Our results suggest that, in addition to the 12q13–15 amplification, NF1 inactivation mutation and other CNAs may contribute to DDLPS tumorigenesis accompanied by aggressive clinical features.
01 Jan 2016
TL;DR: This dissertation begins with unsupervised single--platform analysis, then combines multiple platforms, and finally analyze many data platforms using semi--supervised analysis, showing that TCGA--defined molecular subtypes of glioblastoma are independent of both tumor location and volume, and that both the imaging and genomic data provide important perspectives of the disease.
Abstract: Advancements in sequencing technology have led to an influx of cancer genomics data, transforming cancer research into a field limited by data interpretation rather than acquisition. Machine learning methods that can make use of this wealth of data are desperately needed. Similarly, patient stratification is a critical task in cancer diagnosis and treatment. While stratification approaches using various biomarkers for patient-to-patient comparisons have been successful in elucidating previously unseen subtypes, the potential of many other sparse but rich genotype and phenotype data (e.g. tumor images) remains untapped. To this end, I present two methods. The first uses social network analysis techniques to extract subtypes from sparse data. The second is a semi-supervised multiview learning framework that integrates both prior knowledge and a variety of genomic data to predict outcomes in cancer. Crucially, this method accommodates samples for which we have different data types, paving the way for integration of data from past studies.I apply these methods to several cancer datasets. Of note, I show that TCGA--defined molecular subtypes of glioblastoma are independent of both tumor location and volume, and that both the imaging and genomic data provide important perspectives of the disease. Analysis of a large drug sensitivity database identifies an epigenetic effect from chromatin modifiers that lends sensitivity to Panobinostat. Multiview learning, the second method I developed, also outperforms other methods in predicting sensitivity in all of the study drugs. In this dissertation I begin with unsupervised single--platform analysis, then combine multiple platforms, and finally analyze many data platforms using semi--supervised analysis.
Cites background from "Keeping p53 in check: essential and..."
...Thus, increased MDM4, a molecule that binds to p53 and inhibits its transcriptional functions [230], may provide a mechanism for low p53 signatures in non-TP53 mutated HCCs [85]....
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TL;DR: In this article , the synthesis and characterization of quinolinol derivatives for the identification of analogs that are capable of targeting the MDM2-MDM4 heterodimer E3 ligase and inducing apoptosis in cells.
Abstract: MDM2 and MDM4 are cancer drug targets validated in multiple models for p53-based cancer therapies. The RING domains of MDM2 and non-p53-binder MDM2 splice isoforms form RING domain heterodimer polyubiquitin E3 ligases with MDM4, which regulate p53 stability in vivo and promote tumorigenesis independent of p53. Despite the importance of the MDM2 RING domain in p53 regulation and cancer development, small molecule inhibitors targeting the E3 ligase activity of MDM2-MDM4 are poorly explored. Here, we describe the synthesis and characterization of quinolinol derivatives for the identification of analogs that are capable of targeting the MDM2-MDM4 heterodimer E3 ligase and inducing apoptosis in cells. The structure-activity-relationship (SAR) study identified structural moieties critical for the inhibitory effects toward MDM2-MDM4 E3 ligase, the targeted degradation of MDM4 and FTH1 in cells, and anti-proliferation activity. Lead optimization led to the development of compound MMRi71 with improved activity. In addition to accumulating p53 proteins in wt-p53 bearing cancer cells as expected of any MDM2 inhibitors, MMRi71 effectively kills p53-null leukemia cells, an activity that conventional MDM2-p53 disrupting inhibitors lack. This study provides a prototype structure for developing MDM4/FTH1 dual-targeting inhibitors as potential cancer therapeutics.
TL;DR: In this article , a small-molecule USP2 inhibitor and an anti-PD1 monoclonal antibody were combined to complete regression of the tumors expressing wild-type p53.
Abstract: Abstract Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2 , knockout of Usp2 in mice has no obvious effect in normal tissues. Moreover, no obvious toxicity is observed upon the USP2 inhibitor treatment in vivo as Mdm2-mediated regulation of p53 remains intact. Our study reveals a promising strategy for p53-based therapy by circumventing the toxicity issue.
01 Jan 2014
TL;DR: Interest in TP53 alteration in HNC has undergone a minor renaissance with the observation that some mutations which disrupt the DNA-binding function of p53 are associated with more aggressive cancer phenotype than are mutations that are nondisruptive.
Abstract: Alteration of the TP53 tumor suppressor gene is a central event in the development of human malignancy. The majority of squamous cell carcinomas of the head and neck (HNC) have undergone this molecular disruption either by point mutation of TP53 or through disruption of p53 protein function as a consequence of oncogenic human papillomavirus (HPV) infection. p53 interactions with partner proteins control key cellular pathways that affect apoptosis, the cell cycle, and proliferation, particularly in response to stress. Early research demonstrated mutation in the coding region of TP53 in more than half of all HNC tumors. However, the anticipated value of TP53 alteration for clinical management of HNC has not materialized. This is due, in part, to the complexity of TP53 alterations, which occur at numerous loci within the gene and produce highly variable results with regard to protein function, as well as to the highly integrated position of p53 within densely connected cellular pathways that induce pleiotropic effects. Furthermore, as a tumor suppressor, p53 is not immediately accessible as a therapeutic target, since the restoration of protein activity is more difficult to achieve than the blockage of activity of a gain-of-function event. However, interest in TP53 alteration in HNC has undergone a minor renaissance with the observation that some mutations which disrupt the DNA-binding function of p53 are associated with more aggressive cancer phenotype than are mutations that are nondisruptive. Identification and targeting of this class of TP53 mutation may, hence, have clinical importance in the disease management of HNC. We summarize current relevant issues in TP53 biology.
Cites background from "Keeping p53 in check: essential and..."
...MDM2/MDM4 interaction with the C-terminal ring domains [111]....
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References
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TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
8,339 citations
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
Abstract: MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.
4,397 citations
TL;DR: It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
Abstract: The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
4,311 citations
TL;DR: It is shown that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation, which may contribute to the maintenance of low p53 concentrations in normal cells.
Abstract: The tumour-suppressor p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Stabilization of the protein in response to an activating signal, such as DNA damage, results in a rapid rise in p53 levels and subsequent inhibition of cell growth. Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein. Mdm2 inhibits p53 cell-cycle arrest and apoptic functions and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation. Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpression of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53, this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells. Furthermore, mechanisms regulating the Mdm2-induced degradation of p53 may play a role in controlling the extent and duration of the p53 response.
3,298 citations
TL;DR: The data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus‐uninfected cells which do not have E6 protein.
1,962 citations