scholarly journals GROWTH INHIBITION OF MURINE TUMOR CELLS, IN VITRO, BY PUROMYCIN, [6N]O2'-DIBUTYRYL 3',5'-ADENOSINE MONOPHOSPHATE, OR ADENOSINE

1973 ◽  
Vol 57 (2) ◽  
pp. 397-405 ◽  
Author(s):  
D. B. Thomas ◽  
Gay Medley ◽  
C. A. Lingwood
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Growth Arrest ◽  
Adenosine Monophosphate ◽  
Synchronous Cultures ◽  
Murine Tumor Cells

The cytostatic effects of puromycm, [6N]O2'-dibutyryl 3',5'-adenosine monophosphate, and adenosine on asynchronous and synchronous cultures of the murine mastocytoma, P815Y, have been studied. Cell growth was arrested after a minimum of one further division. A model is proposed for the inhibition of cell division in which the periods of inhibition and growth arrest are separated in time by one cell cycle.

scholarly journals SAT-LB138 The LncRNA Growth Arrest Specific 5 Regulates Cell Survival via Distinct Structural Modules With Independent Functions

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Filipp Frank ◽  
Nadieh Kavousi ◽  
Aikaterina Bountali ◽  
Eric Dammer ◽  
Mirna Mourtada-Maarabouni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cell Growth ◽  
Secondary Structure ◽  
Cell Survival ◽  
Growth Arrest ◽  
B Cell Lymphoma ◽  
Mtor Inhibition ◽  
Core Module

Abstract The growth arrest-specific 5 (gas5) gene encodes a long non-coding RNA (lncRNA) that is required for normal growth arrest, slows down the cell cycle, controls apoptosis, and is required for the inhibition of cell growth by mTOR inhibitors such as rapamycin. In agreement with this role in regulating cell proliferation, Gas5 expression is reduced and acts as a tumor suppressor in numerous cancers, including B-cell lymphoma and leukemia. At its 3’ terminal end (nucleotides 546-566) Gas5 contains a predicted stem-loop structure that specifically interacts with steroid receptors (SRs) and blocks DNA-dependent steroid signalling. In steroid-sensitive cancer cells such as prostate cancers this SR binding motif is responsible for Gas5 effects on cell growth. This is not true in other cell types, however, where proliferation is not strongly dependent on SR signaling (e.g. leukemic T cells). Therefore, other regions in Gas5 must be active and use different mechanisms to regulate cell survival. We have used SHAPE chemical probing to analyze the secondary structure of Gas5 in vitro and in cellulo. We find that the secondary structure of endogenous Gas5 resembles that of in vitro transcribed Gas5 RNA. The molecule contains three separate structural modules: a 5’ module with low secondary structure content, a highly structured core module, and the SR binding module, which forms separate from the rest of the molecule close to its 3’ end. Functional studies in leukemic T cells show that the 5’ module mediates Gas5’s role in inhibiting basal cell survival and slowing the cell cycle, whereas the core module is required for mediating the effects of mTOR inhibition. These results confirm that the Gas5 structural modules function independently in cells and each module acts under different cellular conditions, likely using different molecular mechanisms. RNA pull-downs from cell lysates using the identified modules and full-length RNA identified proteins preferentially associated with each module. Proteins preferentially associated with the 5’ terminal region are enriched in splicing and RNA processing factors. The structured central region preferentially interacts with proteins involved in chromosome organization such as the SWI/SNF family of nucleosome remodeling complexes.

Jab1-siRNA Induces Cell Growth Inhibition and Cell Cycle Arrest in Gall Bladder Cancer Cells via Targeting Jab1 Signalosome

2020 ◽  
Vol 19 (16) ◽  
pp. 2019-2033 ◽  
Author(s):  
Pratibha Pandey ◽  
Mohammad H. Siddiqui ◽  
Anu Behari ◽  
Vinay K. Kapoor ◽  
Kumudesh Mishra ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Cell Growth ◽  
Gall Bladder ◽  
Growth Inhibition ◽  
Cell Cycle Arrest ◽  
Gall Bladder Cancer ◽  
Cell Growth Inhibition ◽  
Cycle Arrest ◽  
Apoptotic Induction

Background: The aberrant alteration in Jab1 signalosome (COP9 Signalosome Complex Subunit 5) has been proven to be associated with the progression of several carcinomas. However the specific role and mechanism of action of Jab1 signalosome in carcinogenesis of gall bladder cancer (GBC) are poorly understood. Objective: The main objective of our study was to elucidate the role and mechanism of Jab1 signalosome in gall bladder cancer by employing siRNA. Methods: Jab1 overexpression was identified in gall bladder cancer tissue sample. The role of Jab1-siRNA approach in cell growth inhibition and apoptotic induction was then examined by RT-PCR, Western Blotting, MTT, ROS, Hoechst and FITC/Annexin-V staining. Results: In the current study, we have shown that overexpression of Jab1 stimulated the proliferation of GBC cells; whereas downregulation of Jab1 by using Jab1-siRNA approach resulted incell growth inhibition and apoptotic induction. Furthermore, we found that downregulation of Jab1 induces cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene. Moreover, Jab1-siRNA induces apoptosis by enhancing ROS generation and caspase-3 activation. In addition, combined treatment with Jab1-siRNA and gemicitabine demonstrated an enhanced decline in cell proliferation which further suggested increased efficacy of gemcitabine at a very lower dose (5μM) in combination with Jab1-siRNA. Conclusion: In conclusion, our study strongly suggests that targeting Jab1 signalosome could be a promising therapeutic target for the treatment of gall bladder cancer.

scholarly journals Effect of β-carotene-rich tomato lycopene β-cyclase (tlcy-b) on cell growth inhibition in HT-29 colon adenocarcinoma cells

2008 ◽  
Vol 102 (2) ◽  
pp. 207-214 ◽  
Author(s):  
Paola Palozza ◽  
Diana Bellovino ◽  
Rossella Simone ◽  
Alma Boninsegna ◽  
Francesco Cellini ◽  
...  
Keyword(s):  
Cell Growth ◽  
Growth Inhibition ◽  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Cell Growth Inhibition ◽  
Adenocarcinoma Cells ◽  
Ht 29 ◽  
Colon Adenocarcinoma Cells ◽  
Β Carotene

Lycopene β-cyclase (tlcy-b) tomatoes, obtained by modulating carotenogenesis via genetic engineering, contain a large amount of β-carotene, as clearly visible by their intense orange colour. In the present study we have subjected tlcy-b tomatoes to an in vitro simulated digestion and analysed the effects of digestate on cell proliferation. To this aim we used HT-29 human colon adenocarcinoma cells, grown in monolayers, as a model. Digested tomatoes were diluted (20 ml, 50 ml and 100 ml/l) in culture medium and added to the cells for different incubation times (24 h, 48 h and 72 h). Inhibition of cell growth by tomato digestate was dose-dependent and resulted from an arrest of cell cycle progression at the G0/G1 and G2/M phase and by apoptosis induction. A down-regulation of cyclin D1, Bcl-2 and Bcl-xl expression was observed. We also found that heat treatment of samples before digestion enhanced β-carotene release and therefore cell growth inhibition. To induce with purified β-carotene solubilised in tetrahydrofuran the same cell growth inhibition obtained with the tomato digestate, a higher amount of the carotenoid was necessary, suggesting that β-carotene micellarised during digestion is utilised more efficiently by the cells, but also that other tomato molecules, reasonably made available during digestion, may be present and cooperate with β-carotene in promoting cell growth arrest.

Echinococcus multilocularis: In vitro secretion of antigen by hybridomas from metacestode germinal cells and murine tumor cells

1989 ◽  
Vol 68 (2) ◽  
pp. 186-191 ◽  
Author(s):  
Angela Dieckmann-Schuppert ◽  
Andreas Ruppel ◽  
Reinhard Burger ◽  
Werner Frank
Keyword(s):  
Tumor Cells ◽  
Echinococcus Multilocularis ◽  
Murine Tumor ◽  
Germinal Cells ◽  
Murine Tumor Cells

scholarly journals Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

2018 ◽  
Author(s):  
Evgeny Zatulovskiy ◽  
Daniel F. Berenson ◽  
Benjamin R. Topacio ◽  
Jan M. Skotheim
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Growth ◽  
Cell Size ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Inverse Correlation ◽  
Cell Types ◽  
Similar Amount ◽  
Cell Cycle Inhibitor

Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, biosynthesis, and surface transport1,2. Tiny erythrocytes squeeze through capillaries to transport oxygen, while the million-fold larger oocyte divides without growth to form the ~100 cell pre-implantation embryo. Despite the vast size range across cell types, cells of a given type are typically uniform in size likely because cells are able to accurately couple cell growth to division3–6. While some genes whose disruption in mammalian cells affects cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive7–12. Here, we show that cell growth acts to dilute the cell cycle inhibitor Rb to drive cell cycle progression from G1 to S phase in human cells. In contrast, other G1/S regulators remained at nearly constant concentration. Rb is a stable protein that is synthesized during S and G2 phases in an amount that is independent of cell size. Equal partitioning to daughter cells of chromatin bound Rb then ensures that all cells at birth inherit a similar amount of Rb protein. RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rb-dilution by cell growth in G1 provides a long-sought cell autonomous molecular mechanism for cell size homeostasis.

scholarly journals Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1844-1844
Author(s):  
John Richards ◽  
Myriam N Bouchlaka ◽  
Robyn J Puro ◽  
Ben J Capoccia ◽  
Ronald R Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Tumor Growth Inhibition ◽  
Employment Equity ◽  
Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

scholarly journals Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1

2021 ◽  
Author(s):  
Rosemarie E. Gough ◽  
Matthew C. Jones ◽  
Thomas Zacharchenko ◽  
Shimin Le ◽  
Miao Yu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Adhesion ◽  
Cell Division ◽  
Mechanical Response ◽  
Direct Interaction ◽  
Cyclin Dependent Kinase ◽  
Cell Cycle Regulator ◽  
Direct Binding

AbstractTalin is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behaviour of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronised phosphorylation of a large number of protein targets. CDK1 activity also maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesiveness that are required for successful completion of mitosis. Using a combination of biochemical, structural and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8 through the use of recombinant fragments. Talin also contains a consensus CDK1 phosphorylation motif centred on S1589; a site that was phosphorylated by CDK1in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of KANK and weakened the mechanical response of the region, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, therefore provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division in multicellular organisms.SummaryThe direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division.

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