p53 Activation by Small Molecules:  Application in Oncology

2005 ◽  
Vol 48 (14) ◽  
pp. 4491-4499 ◽  
Author(s):  
Lyubomir T. Vassilev
Keyword(s):  
Small Molecules ◽  
P53 Activation

scholarly journals Novel Allosteric Mechanism of P53 Activation by Small Molecules for Targeted Anticancer Therapy

2018 ◽  
Author(s):  
Joanna Zawacka-Pankau ◽  
Vera V. Grinkevich ◽  
Mikhail Burmakin ◽  
Aparna Vema ◽  
Karin Ridderstråle ◽  
...  
Keyword(s):  
Small Molecules ◽  
Anticancer Therapy ◽  
Allosteric Mechanism ◽  
P53 Activation

scholarly journals TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Katerina Leonova ◽  
Alfiya Safina ◽  
Elimelech Nesher ◽  
Poorva Sandlesh ◽  
Rachel Pratt ◽  
...  
Keyword(s):  
Small Molecules ◽  
Mammalian Cells ◽  
Genomic Stability ◽  
Cellular Responses ◽  
Dna Demethylation ◽  
Interferon Response ◽  
Dependent Manner ◽  
Dna Interactions ◽  
P53 Activation ◽  
Nf Kappab

Cellular responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anticancer activity of curaxin, previously attributed to p53-activation and NF-kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular ‘repeatome’. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin.

p53 Activation by Small Molecules: Application in Oncology

ChemInform ◽  
2005 ◽  
Vol 36 (40) ◽  
Author(s):  
Lyubomir T. Vassilev
Keyword(s):  
Small Molecules ◽  
P53 Activation

Expression of JAZ in Multiple Myeloma and Its Potential Role as A Novel Molecular Target.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2862-2862
Author(s):  
Mingli Yang ◽  
Jingxin Qiu ◽  
Ying Li ◽  
David Ostrov ◽  
Jinghua Jia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Death ◽  
Small Molecules ◽  
Normal Tissue ◽  
Potential Role ◽  
Plasma Cells ◽  
Hematologic Malignancies ◽  
Molecular Target ◽  
P53 Activation

Abstract Abstract 2862 Poster Board II-838 Multiple myeloma (MM) is an incurable hematologic tumor caused by malignant transformation of plasma cells. JAZ (just another zinc finger protein) was previously identified in our laboratory as a unique ZFP that preferentially binds to double-stranded (ds) RNA rather than dsDNA. The JAZ gene is localized to the human chromosome 5q35-ter, which is a specific chromosomal region at which deletions and translocations occur in different hematologic malignancies including multiple myeloma. The NCI Cancer Genome Anatomy Project data base search reveals that a validated SNP (single nucleotide polymorphism) exists for JAZ at an evolutionarily conserved, 3'-untranslated, regulatory region of JAZ mRNA. This specific SNP exists only in the bone marrow cancer but not in the normal tissue, suggesting a potential role for JAZ in hematologic malignancies. Importantly, we recently discovered JAZ as a novel direct, positive regulator of p53 transcriptional activity. The mechanism involves direct binding to p53's C-terminal (negative) regulatory domain to activate “latent” p53 in response to non-genotoxic stress signals. Moreover, we found that interleukin-3 growth factor withdrawal upregulates JAZ expression in factor-dependent hematopoietic cells in association with activation of the p53 tumor suppressor and induction of apoptotic cell death, indicating that the expression of JAZ is important in the stress response. Thus, to examine the role of JAZ expression in hematologic malignancies, we carried out an immunohistochemistry (IHC) study of JAZ expression in murine and human bone marrow cells and in normal and malignant hematologic tissues and cell lines. The affinity-purified rabbit polyclonal antibody JAZ111 was used and its specificity was verified by the peptide inhibition and also using a commercially available monoclonal antibody against JAZ. Results reveal that JAZ is differentially expressed in different types or stages of hematopoietic cells. For instance, morphologically, JAZ appears to be (relatively) abundantly expressed in plasma cells in normal bone marrow samples and such observation was verified by co-staining with a CD38 antibody. Interestingly, results of JAZ111 staining of an MM tissue microarray (24 cases/48 cores, 13 MM and 11 normal tissues) reveal that in ∼50 % of the MM samples the expression of JAZ is substantially down-regulated compared to the normal tissue controls. This supports the notion that JAZ may play a tumor suppressor role. However, there are exceptions that JAZ was found to be highly or over-expressed in some MM samples on the microarray and other regular individual sample slides, suggesting that JAZ may be latent or inactivated in these cases. Co-staining of the MM samples with a p53 antibody shows that expression of p53 is low, which agrees with the notion that p53 expressed in the MM samples is usually the wild type but in a latent state since the p53 gene has been reported to be rarely mutated and the p53 pathway remains intact in multiple myeloma. Thus, we hypothesize that activation or reactivation of JAZ in the MM cells which express abundant but latent JAZ may induce p53 activation to arrest or kill MM cells. We have explored JAZ as a potentially novel molecular target in multiple myeloma by identifying small molecules that bind and activate JAZ. Using a high-throughput, “molecular docking” strategy, we have screened approximately 240,000 small molecules for their ability to interact with JAZ. Based on the Lipinski Rules for Drug Likeness (molecular characteristics favorable for absorption and permeability), we identified ∼70 putative “drug-like” binding molecules with high scores and obtained ∼40 of them from the NCI Developmental Therapeutics Program. We performed the cell viability study, flow cytometry and Western blot analysis to test their effect on the MM cell lines. Results demonstrate that several of the “candidate” JAZ-targeting compounds can potently induce growth arrest and/or cell death in association with p53 activation. Therefore, while further in vitro and in vivo characterization remains to be carried out, the JAZ-“targeting” compounds point the way to develop a potentially novel therapeutic strategy targeting JAZ to treat multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

2018 ◽  
Author(s):  
Joanna Zawacka-Pankau ◽  
Vera V. Grinkevich ◽  
Mikhail Burmakin ◽  
Aparna Vema ◽  
Karin Fawkner ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Small Molecules ◽  
Anticancer Therapy ◽  
Mechanisms Of Action ◽  
Allosteric Modulation ◽  
Structural Element ◽  
Allosteric Mechanism ◽  
Anti Cancer ◽  
P53 Activation ◽  
Pharmacological Potential

AbstractGiven the immense significance of p53 restoration for anti-cancer therapy, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in p53 regulation, whose targeting by RITA, PpIX and licofelone block the binding of p53 inhibitors, MDM2 and MDMX. Deletion and mutation analysis followed by molecular modeling, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators. Our study provides the basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacological potential.

Relative apoptotic potential and specific G1 arrest of stigmasterol and cinnamic acid isolated from the brown algae Padina gymnospora in HeLa and A549 cells

MedChemComm ◽  
2016 ◽  
Vol 7 (7) ◽  
pp. 1429-1435 ◽  
Author(s):  
Veeresh Kumar Sali ◽  
Debjani P. Mansingh ◽  
Hannah R. Vasanthi
Keyword(s):  
Small Molecules ◽  
Molecular Mechanism ◽  
Cinnamic Acid ◽  
Brown Algae ◽  
East Coast ◽  
A549 Cells ◽  
G1 Arrest ◽  
East Coast Of India ◽  
Padina Gymnospora ◽  
P53 Activation

Isolation, characterisation and identification of the molecular mechanism of apoptosis by small molecules from the Padina gymnospora of south east coast of India revealed that they exhibit tumor suppression mediated by p53 activation.

Gap junctions in the prothoracic glands of the tobacco hornworm, Manduca sexta

1992 ◽  
Vol 50 (1) ◽  
pp. 706-707
Author(s):  
Ji-da Dai ◽  
M. Joseph Costello ◽  
Lawrence I. Gilbert
Keyword(s):  
Gap Junctions ◽  
Small Molecules ◽  
Manduca Sexta ◽  
Freeze Fracture ◽  
Cell Communication ◽  
Cellular Level ◽  
Thin Sections ◽  
Prothoracic Glands ◽  
Polyhydroxylated Steroids ◽  
Stimulation Of

Insect molting and metamorphosis are elicited by a class of polyhydroxylated steroids, ecdysteroids, that originate in the prothoracic glands (PGs). Prothoracicotropic hormone stimulation of steroidogenesis by the PGs at the cellular level involves both calcium and cAMP. Cell-to-cell communication mediated by gap junctions may play a key role in regulating signal transduction by controlling the transmission of small molecules and ions between adjacent cells. This is the first report of gap junctions in the PGs, the evidence obtained by means of SEM, thin sections and freeze-fracture replicas.

Fusion and Fission Processes in Exocytosis: Possible Roles for Synexin and Osmotic Lysis in the Two Events

1980 ◽  
Vol 38 ◽  
pp. 594-597
Author(s):  
H.B. Pollard ◽  
C.E. Creutz ◽  
C.J. Pazoles ◽  
J.H. Scott
Keyword(s):  
Small Molecules ◽  
Chromaffin Cells ◽  
Adrenal Glands ◽  
General Concept ◽  
Extracellular Calcium ◽  
Large Protein ◽  
Granule Membrane ◽  
Osmotic Lysis ◽  
Per Se ◽  
Chemical Evidence

Exocytosis is a general concept describing secretion of enzymes, hormones and transmitters that are otherwise sequestered in intracellular granules. Chemical evidence for this concept was first gathered from studies on chromaffin cells in perfused adrenal glands, in which it was found that granule contents, including both large protein and small molecules such as adrenaline and ATP, were released together while the granule membrane was retained in the cell. A number of exhaustive reviews of this early work have been published and are summarized in Reference 1. The critical experiments demonstrating the importance of extracellular calcium for exocytosis per se were also first performed in this system (2,3), further indicating the substantial service given by chromaffin cells to those interested in secretory phenomena over the years.

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