scholarly journals RAG-induced DNA lesions activate proapoptotic BIM to suppress lymphomagenesis in p53-deficient mice

2016 ◽  
Vol 213 (10) ◽  
pp. 2039-2048 ◽  
Author(s):  
Alex R.D. Delbridge ◽  
Swee Heng Milon Pang ◽  
Cassandra J. Vandenberg ◽  
Stephanie Grabow ◽  
Brandon J. Aubrey ◽  
...  
Keyword(s):  
Gene Rearrangement ◽  
Apoptotic Cell ◽  
Receptor Gene ◽  
Dna Lesions ◽  
Multiple Tumor ◽  
Tumor Susceptibility ◽  
Cycle Arrest ◽  
Replication Gene ◽  
Deficient Mice

Neoplastic transformation is driven by oncogenic lesions that facilitate unrestrained cell expansion and resistance to antiproliferative signals. These oncogenic DNA lesions, acquired through errors in DNA replication, gene recombination, or extrinsically imposed damage, are thought to activate multiple tumor suppressive pathways, particularly apoptotic cell death. DNA damage induces apoptosis through well-described p53-mediated induction of PUMA and NOXA. However, loss of both these mediators (even together with defects in p53-mediated induction of cell cycle arrest and cell senescence) does not recapitulate the tumor susceptibility observed in p53−/− mice. Thus, potentially oncogenic DNA lesions are likely to also trigger apoptosis through additional, p53-independent processes. We found that loss of the BH3-only protein BIM accelerated lymphoma development in p53-deficient mice. This process was negated by concomitant loss of RAG1/2-mediated antigen receptor gene rearrangement. This demonstrates that BIM is critical for the induction of apoptosis caused by potentially oncogenic DNA lesions elicited by RAG1/2-induced gene rearrangement. Furthermore, this highlights the role of a BIM-mediated tumor suppressor pathway that acts in parallel to the p53 pathway and remains active even in the absence of wild-type p53 function, suggesting this may be exploited in the treatment of p53-deficient cancers.

scholarly journals Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Hang Gao ◽  
Siyue Lou ◽  
Huanwu Hong ◽  
Qiufu Ge ◽  
Huajun Zhao
Keyword(s):  
Apoptotic Cell ◽  
Single Agent ◽  
Acid Group ◽  
Lymphocytic Leukemia ◽  
Cyclin E1 ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Histone Hyperacetylation ◽  
Autophagy Inhibition

Acute T lymphocytic leukemia (T-ALL) is an aggressive hematologic resulting from the malignant transformation of T-cell progenitors. Drug resistance and relapse are major difficulties in the treatment of T-ALL. Here, we report the antitumor potency of NL-101, a compound that combines the nitrogen mustard group of bendamustine with the hydroxamic acid group of vorinostat. We found NL-101 exhibited efficient antiproliferative activity in T-ALL cell lines (IC50 1.59–1.89 μM), accompanied by cell cycle arrest and apoptosis, as evidenced by the increased expression of Cyclin E1, CDK2, and CDK4 proteins and cleavage of PARP. In addition, this bendamustine-derived drug showed both a HDACi effect as demonstrated by histone hyperacetylation and p21 transcription and a DNA-damaging effect as shown by an increase in γ-H2AX. Intriguingly, we found that NL-101-induced autophagy in T-ALL cells through inhibiting Akt-mTOR signaling pathway, as indicated by an increase in LC3-I to LC3-II conversion and decrease of p62. Furthermore, inhibition of autophagy by 3-methyladenine increased apoptotic cell death by NL-101, suggesting a prosurvival role of autophagy. In summary, our finding provides rationale for investigation of NL-101 as a DNA/HDAC dual targeting drug in T-ALL, either as a single agent or in combination with autophagy inhibitors.

scholarly journals Role of Interleukin-18 in Modulation of Oral Carcinoma Cell Proliferation

2006 ◽  
Vol 2006 ◽  
pp. 1-6 ◽  
Author(s):  
Athip Nilkaeo ◽  
Suthinee Bhuvanath
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Tumor Regression ◽  
Apoptotic Cell ◽  
Interleukin 18 ◽  
Cycle Arrest ◽  
Dose Dependent Fashion ◽  
Oral Cancer Cells

Interleukin-18 (IL-18), a proinflammatory cytokine, is produced by oral epithelia and carcinoma cells and implicated in tumor regression. Since its direct biological effect on oral cancer cells is not well defined, in this study, we employed a KB cell line to test IL-18 activity. Recombinant human IL-18 significantly inhibited KB cell proliferation in a dose-dependent fashion (P<.05) without increasing cytotoxicity. Analysis of its mode of action showed that IL-18 induced cell cycle arrest in the S phase; however, it did not trigger apoptotic cell death. Findings in this study indicate that the suppression of KB cell proliferation was attributed to the modulation of cell cycle progression, providing a new role of this cytokine in antitumor mechanisms.

scholarly journals The Role of Molecular Pathology in the Diagnosis of Cutaneous Lymphomas

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Philipp W. Raess ◽  
Adam Bagg
Keyword(s):  
Molecular Pathology ◽  
Gene Rearrangement ◽  
Receptor Gene ◽  
Clinical Findings ◽  
Molecular Assays ◽  
Cutaneous Lymphomas ◽  
Molecular Studies ◽  
Ancillary Studies ◽  
Biologic Basis

Primary cutaneous lymphomas can be difficult to be distinguished from reactive mimics, even when integrating histologic, immunophenotypic, and clinical findings. Molecular studies, especially PCR-based antigen receptor gene rearrangement (ARGR) analysis, are frequently useful ancillary studies in the evaluation of cutaneous lymphoproliferations. The biologic basis of ARGR studies is discussed, as well as a comparison of various current protocols. The pitfalls and limitations of ARGR analysis are also highlighted. Recent advances in the understanding of the molecular pathogenesis of various cutaneous lymphomas are discussed. Some of these nascent discoveries may lead to the development of diagnostically useful molecular assays.

Abstract 102: The Detrimental Role Of iPLA2β In Ischemia/reperfusion Injury

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Hitomi Matsuga ◽  
Osamu Yamaguchi ◽  
Yoshihide Tsujimoto ◽  
Kinya Otsu
Keyword(s):  
Cell Death ◽  
Cardiac Function ◽  
Genomic Library ◽  
Apoptotic Cell ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Apoptotic Cell Death ◽  
Mouse Heart ◽  
Deficient Mice

Background: Ca 2+ -independent phospholipase A2 (iPLA2) is crucial for a caspase-independent non-apoptotic cell death signaling pathway and involved in nuclear shrinkage induced by hypoxia. PLA2 family hydrolyzes the sn-2 ester bond in phospholipids to release free fatty acids and lysophospholipids. PLA2 inhibitors are known to prevent ischemic-reperfusion (I/R) injury. Here, we attempted to clarify the role of iPLA2β in myocardial I/R injury using cardiac-specific iPLA2β-deficient mice. Methods: Pla2g6 gene-targeting vector was constructed using mouse BAC genomic library. The ES clones with targeted homologous recombination were injected into blastocyst mouse embryos. Floxed iPLA2β mice were crossed with transgenic mice expressing Cre recombinase under the control of the α-myosin heavy chain ( αMHC ) promoter to generate cardiac-specific iPLA2β-deficient mice ( pla2g6 flox/flox αMHC-Cre + : CKO). We used pla2g6 flox/flox αMHC-Cre - littermates as controls (CTRL). We performed transthoracic M-mode echocardiographic analysis to examine the cardiac function of CKO and CTRL. Next, we subjected CKO and CTRL to I/R injury by using Langendorff-perfused mouse heart model. The heart was subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. After the reperfusion, infarct area was determined with 1% triphenyltetrazolium chloride, and apoptotic cell death was detected by in situ TUNEL assay on heart sections. We exposed isolated adult cardiomyocytes from CKO and CTRL to various stimuli, such as Ca 2+ ionophore, H 2 O 2 and staurosporine, to examine the involvement of necrosis and apoptosis. Results: CKO and CTRL mice were born at the expected Mendelian ratio. There were no differences in cardiac function between CKO and CTRL. The functional recovery during reperfusion was significantly greater in CKO than in CTRL. CKO exhibited a significant decrease in the size of myocardial infarct. There were no significant differences in necrotic cell death induced by necrotic stimuli in vitro, while apoptotic cell death tended to decrease in CKO heart. Conclusions: These results suggest that iPLA2β exacerbates apoptotic cell death in I/R.

scholarly journals Conditional Inactivation of Glucocorticoid Receptor Gene in Dopamine-β-Hydroxylase Cells Impairs Chromaffin Cell Survival

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1775-1781 ◽  
Author(s):  
Rosanna Parlato ◽  
Christiane Otto ◽  
Jan Tuckermann ◽  
Stefanie Stotz ◽  
Sylvia Kaden ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Chromaffin Cells ◽  
Chromaffin Cell ◽  
Apoptotic Cell ◽  
Receptor Gene ◽  
Adrenal Chromaffin Cells ◽  
Glucocorticoid Receptor Gene ◽  
Conditional Inactivation ◽  
Adrenal Chromaffin

Glucocorticoid hormones (GCs) have been thought to determine the fate of chromaffin cells from sympathoadrenal progenitor cells. The analysis of mice carrying a germ line deletion of the glucocorticoid receptor (GR) gene has challenged these previous results because the embryonic development of adrenal chromaffin cells is largely unaltered. In the present study, we have analyzed the role of GC-dependent signaling in the postnatal development of adrenal chromaffin cells by conditional inactivation of the GR gene in cells expressing dopamine-β-hydroxylase, an enzyme required for the synthesis of noradrenaline and adrenaline. These mutant mice are viable, allowing to study whether in the absence of GC signaling further development of the adrenal medulla is affected. Our analysis shows that the loss of GR leads not only to the loss of phenylethanolamine-N-methyl-transferase expression and, therefore, to inhibition of adrenaline synthesis, but also to a dramatic reduction in the number of adrenal chromaffin cells. We provide evidence that increased apoptotic cell death is the main consequence of GR loss. These findings define the essential role of GCs for survival of chromaffin cells and underscore the specific requirement of GCs for adrenergic chromaffin cell differentiation and maintenance.

The Estimation of prostate specific antigen (PSA) concentrations in patients with prostatitis by fully automated ELISA technique.

2020 ◽  
Vol 3 (11) ◽  
pp. 1100-1104
Author(s):  
Hussein Naeem Aldhaheri ◽  
Ihsan Edan AlSaimary ◽  
Murtadha Mohammed ALMusafer
Keyword(s):  
Personal Information ◽  
Receptor Gene ◽  
Specific Antigen ◽  
Gene Clusters ◽  
Control Group ◽  
P Value ◽  
Group Data ◽  
Elisa Technique ◽  
And Control

      The Aim of this study was to determine Immunogenetic expression of  Toll-like receptor gene clusters related to prostatitis, to give acknowledge about Role of TLR in prostatitis immunity in men from Basrah and Maysan provinces. A case–control study included 135 confirmed prostatitis patients And 50 persons as a control group. Data about age, marital status, working, infertility, family history and personal information like (Infection, Allergy, Steroid therapy, Residency, Smoking, Alcohol Drinking, Blood group, Body max index (BMI) and the clinical finding for all patients of Prostatitis were collected. This study shows the effect of PSA level in patients with prostatitis and control group, with P-value <0.0001 therefore the study shows a positive significant between elevated PSA levels and Prostatitis.

Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

2020 ◽  
Vol 15 (6) ◽  
pp. 482-491 ◽  
Author(s):  
Milena Kostadinova ◽  
Milena Mourdjeva
Keyword(s):  
Cancer Cells ◽  
Small Population ◽  
Tumor Formation ◽  
Bioactive Molecules ◽  
Cancer Therapies ◽  
New Methods ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

The Hormonal Underpinnings of Sexual Communication

2020 ◽  
pp. 234-260
Author(s):  
Amanda Denes ◽  
Anuraj Dhillon ◽  
Ambyre L. P. Ponivas ◽  
Kara L. Winkler
Keyword(s):  
Interpersonal Relationships ◽  
Sexual Communication ◽  
Receptor Gene ◽  
Oxytocin Receptor ◽  
Communication Research ◽  
Future Directions ◽  
Oxytocin Receptor Gene ◽  
Broad Domain ◽  
Relational Outcomes

Sexual communication is a pivotal part of interpersonal relationships; recent research reveals associations between sexual communication and various relational outcomes. Within the broad domain of sexual communication, current scholarship specifically addresses the role of postsex communication in relationships and its links to physiological and genetic markers. Given these advancements, the present chapter offers an overview of research linking physiology, hormones, and genes to communication after sexual activity. The chapter first presents reviews of two key hormones in sexual communication research: testosterone (T) and oxytocin (O). The oxytocin receptor gene and its link to social behavior broadly, and sexual behavior specifically, is also explored. The chapter then offers a review of several theories relevant to understanding the hormonal underpinnings of sexual communication, as well as future directions for research exploring sexual communication and physiology.

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