scholarly journals Bcr-TMP, a Novel Nanomolar-Active Compound That Exhibits Both MYB- and Microtubule-Inhibitory Activity

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 43
Author(s):  
Maria V. Yusenko ◽  
Abhiruchi Biyanee ◽  
Daria Frank ◽  
Leonhard H. F. Köhler ◽  
Mattias K. Andersson ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Drug Target ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Differentiation Markers ◽  
Microtubule Stability ◽  
Transactivation Potential ◽  
Inhibitory Compound

Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Here, we present the initial characterization of 2-amino-4-(3,4,5-trimethoxyphenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (Bcr-TMP), a nanomolar-active MYB-inhibitory compound identified in a screen for novel MYB inhibitors. Bcr-TMP affects MYB function in a dual manner by inducing its degradation and suppressing its transactivation potential by disrupting its cooperation with co-activator p300. Bcr-TMP also interferes with the p300-dependent stimulation of C/EBPβ, a transcription factor co-operating with MYB in myeloid cells, indicating that Bcr-TMP is a p300-inhibitor. Bcr-TMP reduces the viability of AML cell lines at nanomolar concentrations and induces cell-death and expression of myeloid differentiation markers. It also down-regulates the expression of MYB target genes and exerts stronger anti-proliferative effects on MYB-addicted primary murine AML cells and patient-derived ACC cells than on their non-oncogenic counterparts. Surprisingly, we observed that Bcr-TMP also has microtubule-disrupting activity, pointing to a possible link between MYB-activity and microtubule stability. Overall, Bcr-TMP is a highly potent multifunctional MYB-inhibitory agent that warrants further investigation of its therapeutic potential and mechanism(s) of action.

scholarly journals Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

2019 ◽  
Author(s):  
Sindhu Carmen Sivakumaren ◽  
Hyeseok Shim ◽  
Tinghu Zhang ◽  
Fleur M. Ferguson ◽  
Mark R. Lundquist ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Cancer Cell Proliferation ◽  
Lipid Kinase ◽  
Covalent Inhibitors ◽  
Lipid Kinases ◽  
Disordered Loop

SummaryThe PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here we present the discovery and characterization of a novel pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K’s reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

scholarly journals O-GlcNAc Homeostasis Controls Cell Fate Decisions During Hematopoiesis

2018 ◽  
Author(s):  
Zhen Zhang ◽  
Matt P. Parker ◽  
Stefan Graw ◽  
Lesya V. Novikova ◽  
Halyna Fedosyuk ◽  
...  
Keyword(s):  
Cell Fate ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Vital Role ◽  
Leukemia Cells ◽  
Cell Fate Decisions ◽  
Expression Of Genes ◽  
All Trans Retinoic Acid ◽  
Glcnac Transferase

AbstractThe addition of O-GlcNAc (a single β-D-N-acetylglucosamine sugar at serine and threonine residues) by O-GlcNAc transferase (OGT) and removal by O-GlcNAcase (OGA) maintains homeostatic levels of O-GlcNAc. We investigated the role of O-GlcNAc homeostasis in hematopoiesis utilizing G1E-ER4 cells carrying a GATA-1 transcription factor fused to the estrogen receptor (GATA-1ER) that undergo erythropoiesis following the addition of β-estradiol (E2) and myeloid leukemia cells that differentiate into neutrophils in the presence of all-trans retinoic acid. During G1E-ER4 differentiation, a decrease in overall O-GlcNAc levels and an increase in GATA-1 interactions with OGT and OGA were observed. Transcriptome analysis on G1E-ER4 cells differentiated in the presence of Thiamet-G (TMG), an OGA inhibitor, identified expression changes in 433 GATA-1 target genes. Chromatin immunoprecipitation demonstrated that the occupancy of GATA-1, OGT, and OGA atLaptm5gene GATA site was decreased with TMG. Myeloid leukemia cells showed a decline in O-GlcNAc levels during differentiation and TMG reduced the expression of genes involved in differentiation. Sustained treatment with TMG in G1E-ER4 cells prior to differentiation caused a reduction of hemoglobin positive cells during differentiation. Our results show that alterations in O-GlcNAc homeostasis disrupt transcriptional programs causing differentiation errors suggesting a vital role of O-GlcNAcylation in control of cell fate.

MicroRNA Expression Profiles in Acute Myeloid Leukemia with Common Translocations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3181-3181
Author(s):  
Zejuan Li ◽  
Jun Lu ◽  
Miao Sun ◽  
Shuangli Mi ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Expression Profiling ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
In Vivo Models ◽  
Normal Controls ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. It is estimated that 13,410 cases will be diagnosed and 8,990 will die of AML in the United States in 2007 (http://seer.cancer.gov). AML is a genetically diverse hematopoietic malignancy with variable response to treatment. Expression profiling of protein-coding genes using DNA microarray in AML has resulted in inconsistent data from different laboratories. Therefore, further validation of these observations in large cohorts and in independent studies is definitely required before clinical application becomes feasible. Recently, Golub and colleagues described a new, bead-based flow cytometric microRNA (miRNAs, miRs) expression profiling method that could successfully classify tumors. MiRNAs are endogenous ∼22 nucleotide non-coding RNAs, which can function as oncogenes and tumor suppressors. To provide new insights into the complex genetic alterations in leukemogenesis and to identify novel markers for diagnosis and treatment of AML, we performed a genome-wide analysis of miRNA expression profiles using the bead-based method on 54 AML samples with common translocations including t(15;17), t(8;21), inv(16), and 11q23 rearrangement, along with normal controls. In both unsupervised and supervised hierarchical cluster analyses, we observed that t(15;17) samples grouped together as one cluster, as do the 11q23 rearrangement samples. Interestingly, t(8;21) and inv(16), both CBF (core-binding factor) AMLs, grouped together as a unique cluster. Forty-one miRNAs exhibited significantly differential expression between different subtypes of AMLs, and/or between AMLs and normal controls. Notably, expression signature of a minimal number of two, three, and seven miRNAs could be used for class prediction of CBF, t(15;17), and 11q23 rearrangement AMLs, respectively, with an overall diagnostic accuracy of 94–96%. We further showed that overexpression of the two discriminatory miRNAs in CBF AML is associated with epigenetic regulation, rather than DNA copy number amplification. Moreover, several important target genes of these discriminatory miRNAs have also been validated. We are currently exploring the role of these discriminatory miRNAs and their critical target genes in the development of AML using in vitro and in vivo models. This work will enhance our understanding of the biological role of these miRNAs and their targets in leukemogenesis.

Role of lncRNAs in prostate cancer development and progression

2014 ◽  
Vol 395 (11) ◽  
pp. 1275-1290 ◽  
Author(s):  
Melanie Weiss ◽  
Christoph Plass ◽  
Clarissa Gerhauser
Keyword(s):  
Prostate Cancer ◽  
Target Genes ◽  
Current Knowledge ◽  
Prostate Carcinogenesis ◽  
Prostate Cancer Development ◽  
Chromatin Remodeling Complexes ◽  
Regulation Mechanisms ◽  
Functional Analyses

Abstract Prostate cancer (PCa) is the second most common cause of cancer-related deaths in men. Despite advances in the characterization of genomic and epigenetic aberrations contributing to PCa, the etiology of PCa is still far from being understood. Research over the past decade demonstrated the role of long non-coding RNAs (lncRNAs) in deregulation of target genes mainly through epigenetic mechanisms. In PCa, evidence accumulated that hundreds of lncRNAs are dysregulated. Functional analyses revealed their contribution to prostate carcinogenesis by targeting relevant pathways and gene regulation mechanisms including PTEN/AKT and androgen receptor signaling as well as chromatin remodeling complexes. Here we summarize our current knowledge on the roles of lncRNAs in PCa and their potential use as biomarkers for aggressive PCa and as novel therapeutic targets.

The metabolic coregulator RIP140: an update

2010 ◽  
Vol 299 (3) ◽  
pp. E335-E340 ◽  
Author(s):  
Asmaà Fritah ◽  
Mark Christian ◽  
Malcolm G. Parker
Keyword(s):  
Nuclear Receptors ◽  
Posttranslational Modifications ◽  
Energy Homeostasis ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Transcriptional Coregulator ◽  
Peroxisome Proliferator Activated Receptors ◽  
Direct Regulation

RIP140 is a transcriptional coregulator highly expressed in metabolic tissues where it has important and diverse actions. RIP140-null mice show that it plays a crucial role in the control of lipid metabolism in adipose tissue, skeletal muscle, and the liver and is essential for female fertility. RIP140 has been shown to act as a ligand-dependent transcriptional corepressor for metabolic nuclear receptors such as estrogen-related receptors and peroxisome proliferator-activated receptors. The role of RIP140 as a corepressor has been strengthened by the characterization of RIP140-overexpressing mice, although it emerges through several studies that RIP140 can also behave as a coactivator. Nuclear localization of RIP140 is important for controlling transcription of target genes and is subject to regulation by posttranslational modifications. However, cytoplasmic RIP140 has been shown to play a role in the control of metabolism through direct regulation of glucose transport in adipocytes. In this review, we focus on recent advances highlighting the growing importance of RIP140 as a regulator of energy homeostasis.

Genetics of Human Hypertension, the Role of Angiotensinogen. Should It be One of the Drug Target Genes?

Angiology ◽  
2013 ◽  
Vol 65 (4) ◽  
pp. 269-271 ◽  
Author(s):  
Genovefa D. Kolovou ◽  
Sophie Mavrogeni
Keyword(s):  
Drug Target ◽  
Target Genes ◽  
Human Hypertension

scholarly journals Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Debora Giunti ◽  
Chiara Marini ◽  
Benedetta Parodi ◽  
Cesare Usai ◽  
Marco Milanese ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mode Of Action ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Mapk Signaling ◽  
Target Cells ◽  
Inflammatory Phenotype ◽  
Lateral Sclerosis

AbstractMesenchymal stromal/stem cells (MSCs) are characterized by neuroprotective, immunomodulatory, and neuroregenerative properties, which support their therapeutic potential for inflammatory/neurodegenerative diseases, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One mode of action through which MSCs exert their immunomodulatory effects is release of extracellular vesicles that carry proteins, mRNAs, and microRNAs (miRNAs), which, once transferred, modify the function of target cells. We identified nine miRNAs significantly dysregulated in IFN-γ-primed MSCs, but present at different levels in their derived small extracellular vesicles (s-EV). We show that miR-467f and miR-466q modulate the pro-inflammatory phenotype of activated N9 microglia cells and of primary microglia acutely isolated from late symptomatic SOD1G93A mice, a murine ALS model, by downregulating Tnf and Il1b expression. Further analysis of the mode of action of miR-467f and miR-466q indicated that they dampen the pro-inflammatory phenotype of microglia by modulating p38 MAPK signaling pathway via inhibition of expression of their target genes, Map3k8 and Mk2. Finally, we demonstrated that in vivo administration of s-EV leads to decreased expression of neuroinflammation markers in the spinal cord of EAE-affected mice, albeit without affecting disease course. Overall, our data suggest that MSC-derived exosomes could affect neuroinflammation possibly through specific immunomodulatory miRNAs acting on microglia.

scholarly journals CD47 in the Brain and Neurodegeneration: An Update on the Role in Neuroinflammatory Pathways

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3943
Author(s):  
Seyed Mohammad Gheibihayat ◽  
Ricardo Cabezas ◽  
Nikita G. Nikiforov ◽  
Tannaz Jamialahmadi ◽  
Thomas P. Johnston ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Myeloid Leukemia ◽  
Therapeutic Potential ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Ig Superfamily ◽  
The Brain

CD47 is a receptor belonging to the immunoglobulin (Ig) superfamily and broadly expressed on cell membranes. Through interactions with ligands such as SIRPα, TSP-1, integrins, and SH2-domain bearing protein tyrosine phosphatase substrate-1 (SHPS-1), CD47 regulates numerous functions like cell adhesion, proliferation, apoptosis, migration, homeostasis, and the immune system. In this aspect, previous research has shown that CD47 modulates phagocytosis via macrophages, the transmigration of neutrophils, and the activation of T-cells, dendritic cells, and B-cells. Moreover, several studies have reported the increased expression of the CD47 receptor in a variety of diseases, including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), bladder cancer, acute myeloid leukemia (AML), Gaucher disease, Multiple Sclerosis and stroke among others. The ubiquitous expression of the CD47 cell receptor on most resident cells of the CNS has previously been established through different methodologies. However, there is little information concerning its precise functions in the development of different neurodegenerative pathologies in the CNS. Consequently, further research pertaining to the specific functions and roles of CD47 and SIRP is required prior to its exploitation as a druggable approach for the targeting of various neurodegenerative diseases that affect the human population. The present review attempts to summarize the role of both CD47 and SIRP and their therapeutic potential in neurodegenerative disorders.

scholarly journals Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Ankita Sharma ◽  
Rafeeq Mir ◽  
Sanjeev Galande
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Therapeutic Interventions ◽  
The Past ◽  
Epigenetic Machinery ◽  
Cancer Initiation ◽  
And Migration ◽  
Regenerative Therapies

Studies over the past four decades have elucidated the role of Wnt/β-catenin mediated regulation in cell proliferation, differentiation and migration. These processes are fundamental to embryonic development, regeneration potential of tissues, as well as cancer initiation and progression. In this review, we focus on the epigenetic players which influence the Wnt/β-catenin pathway via modulation of its components and coordinated regulation of the Wnt target genes. The role played by crosstalk with other signaling pathways mediating tumorigenesis is also elaborated. The Hippo/YAP pathway is particularly emphasized due to its extensive crosstalk via the Wnt destruction complex. Further, we highlight the recent advances in developing potential therapeutic interventions targeting the epigenetic machinery based on the characterization of these regulatory networks for effective treatment of various cancers and also for regenerative therapies.

scholarly journals Chronoeffects of the Herbal Medicines Puerariae radix and Coptidis rhizoma in Mice: A Potential Role of REV-ERBα

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinming Liu ◽  
Haiman Xu ◽  
Li Zhang ◽  
Shuai Wang ◽  
Danyi Lu ◽  
...  
Keyword(s):  
Drug Target ◽  
Potential Role ◽  
Target Genes ◽  
Herbal Medicines ◽  
Time Dependent ◽  
Dependent Manner ◽  
Active Constituent ◽  
Puerariae Radix ◽  
Coptidis Rhizoma

Identifying drugs with dosing time-dependent effects (chronoeffects) and understanding the underlying mechanisms would help to improve drug treatment outcome. Here, we aimed to determine chronoeffects of the herbal medicines Puerariae radix (PR) and Coptidis rhizoma (CR), and investigate a potential role of REV-ERBα as a drug target in generating chronoeffects. The pharmacological effect of PR on hyperhomocysteinemia in mice was evaluated by measuring total homocysteine, triglyceride levels and lipid accumulation. PR dosed at ZT10 generated a stronger effect on hyperhomocysteinemia than drug dosed at ZT2. Furthermore, PR increased the expression levels of REV-ERBα target genes Bhmt, Cbs and Cth (encoding three key enzymes responsible for homocysteine catabolism), thereby alleviating hyperhomocysteinemia in mice. Moreover, CR attenuated chronic colitis in mice in a dosing time-dependent manner based on measurements of disease activity index, colon length, malondialdehyde/myeloperoxidase activities and IL-1β/IL-6 levels. ZT10 dosing generated a stronger anti-colitis effect as compared to ZT2 dosing. This was accompanied by lower production of colonic inflammatory cytokines (i.e., Nlrp3, IL-1β, IL-6, Tnf-α and Ccl2, REV-ERBα target genes) in colitis mice dosed at ZT10. The diurnal patterns of PR and CR effects were respectively consistent with those of puerarin (a main active constituent of PR, a REV-ERBα antagonist) and berberine (a main active constituent of CR, a REV-ERBα agonist). In addition, loss of Rev-erbα in mice abolished the dosing time-dependency in PR and CR effects. In conclusion, the therapeutic effects of PR and CR depend on dosing time in mice, which are probably attributed to diurnal expression of REV-ERBα as the drug target. Our findings have implications for improving therapeutic outcomes of herbal medicines with a chronotherapeutic approach.

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