scholarly journals spict, a cyst cell-specific gene, regulates starvation-induced spermatogonial cell death in the Drosophila testis

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Ason C.-Y. Chiang ◽  
Heiko Yang ◽  
Yukiko M. Yamashita
Keyword(s):  
Cell Death ◽  
Specific Gene ◽  
Spermatogonial Cell ◽  
Cyst Cell ◽  
Drosophila Testis

Abstract 143: A Novel TAK1 Signaling Network Regulating Programmed Necrosis and Myocardial Remodeling

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Qinghang Liu ◽  
Lei Li ◽  
Yi Chen ◽  
Jessica Doan ◽  
Jeffery Molkentin
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cell Survival ◽  
Cardiac Fibrosis ◽  
Signaling Network ◽  
Specific Gene ◽  
Caspase 8 ◽  
Programmed Necrosis ◽  
Genetic Ablation ◽  
Cell Death Pathway

We recently identified a novel signaling molecule, TAK1 (TGFβ-activated kinase 1, also known as MAP3K7), as a key regulator of the hypertrophic signaling network. Importantly, TAK1 is activated in mouse models of heart failure as well as in diseased human myocardium. Here, we defined a previously unidentified, novel role for TAK1 in promoting cardiac cell survival and homeostasis using cardiac-specific gene-targeted mice. Indeed, cardiac-specific ablation of TAK1 in mice using a Cre-LoxP system showed enhanced pathological cardiac remodeling and massive cell death, and these mice gradually developed heart failure and spontaneous death. Remarkably, ablation of TNF receptor 1 (TNFR1) largely rescued the pathological phenotype of TAK1-deficient mice, preventing early lethality and cardiac fibrosis, suggesting that TNFR1 signaling is critical in mediating adverse remodeling and heart failure associated with TAK1 deficiency. Genetic or pharmacological inactivation of TAK1 in cardiomyocytes markedly induced programmed necrosis and apoptosis in response to TNFα. Conversely, overexpression of the constitutively active TAK1 mutant, or TAK1 plus its activator TAB1, protected cardiomyocytes from TNFα-induced cell death. Mechanistically, inactivation of TAK1 promoted formation of the necroptotic cell death complex consisting of RIP1, RIP3, caspase 8, and FADD. Genetic ablation of RIP1, RIP3, caspase 8, or FADD largely blocked TNFα-induced cell death in TAK1-deficient cells, whereas deletion of Bax/Bak or cyclophilin D showed no effects. Further, IKK/NFκB-mediated cell survival signaling was greatly impaired in TAK1-deficient cardiomyocytes. Taken together, our data indicate that TAK1 functions as a critical “molecular switch” in TNFα-induced programmed necrosis in cardiomyocytes, by interacting with the RIP1/3-caspase 8-FADD cell death pathway as well as the IKK-NFκB cell survival pathway. These findings thus define an important TAK1-mediated cardio-protective signaling network in the heart, which may suggest new therapeutic strategies in the treatment of heart disease.

scholarly journals Germ cell connectivity enhances cell death in response to DNA damage in the Drosophila testis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Kevin L Lu ◽  
Yukiko M Yamashita
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Germ Cell ◽  
Germ Cells ◽  
High Sensitivity ◽  
Next Generation ◽  
Drosophila Testis

Two broadly known characteristics of germ cells in many organisms are their development as a ‘cyst’ of interconnected cells and their high sensitivity to DNA damage. Here we provide evidence that in the Drosophila testis, connectivity serves as a mechanism that confers to spermatogonia a high sensitivity to DNA damage. We show that all spermatogonia within a cyst die synchronously even when only a subset of them exhibit detectable DNA damage. Mutants of the fusome, an organelle that is known to facilitate intracyst communication, compromise synchronous spermatogonial death and reduces overall germ cell death. Our data indicate that a death-promoting signal is shared within the cyst, leading to death of the entire cyst. Taken together, we propose that intercellular connectivity supported by the fusome uniquely increases the sensitivity of the germline to DNA damage, thereby protecting the integrity of gamete genomes that are passed on to the next generation.

Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL

Blood ◽  
2021 ◽  
Author(s):  
Anja Schmitt ◽  
Wendan Xu ◽  
Philip Bucher ◽  
Melanie Grimm ◽  
Martina Konantz ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Expression Profiles ◽  
Therapeutic Option ◽  
Gene Expression Profiles ◽  
B Cell Lymphoma ◽  
Dimethyl Fumarate ◽  
Specific Gene ◽  
Molecular Heterogeneity ◽  
Stat3 Signaling

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a major therapeutic challenge. DLBCL can be classified into at least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad anti-tumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and JAK kinases. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL.

scholarly journals Growth Arrest-Specific Gene 6 (Gas6)/Adhesion Related Kinase (Ark) Signaling Promotes Gonadotropin-Releasing Hormone Neuronal Survival via Extracellular Signal-Regulated Kinase (ERK) and Akt

1999 ◽  
Vol 13 (2) ◽  
pp. 191-201 ◽  
Author(s):  
Melissa P. Allen ◽  
Chan Zeng ◽  
Kristina Schneider ◽  
Xiaoyan Xiong ◽  
Mary Kay Meintzer ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Neuronal Migration ◽  
Neuronal Development ◽  
Mek Inhibitor ◽  
Specific Gene ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Gnrh Neurons ◽  
Induced Apoptosis

Abstract We identified Ark, the mouse homolog of the receptor tyrosine kinase Axl (Ufo, Tyro7), in a screen for novel factors involved in GnRH neuronal migration by using differential-display PCR on cell lines derived at two windows during GnRH neuronal development. Ark is expressed in Gn10 GnRH cells, developed from a tumor in the olfactory area when GnRH neurons are migrating, but not in GT1–7 cells, derived from a tumor in the forebrain when GnRH neurons are postmigratory. Since Ark (Axl) signaling protects from programmed cell death in fibroblasts, we hypothesized that it may play an antiapoptotic role in GnRH neurons. Gn10 (Ark positive) GnRH cells were more resistant to serum withdrawal-induced apoptosis than GT1–7 (Ark negative) cells, and this effect was augmented with the addition of Gas6, the Ark (Axl) ligand. Gas6/Ark stimulated the extracellular signal-regulated kinase, ERK, and the serine-threonine kinase, Akt, a downstream component of the phosphoinositide 3-kinase (PI3-K) pathway. To determine whether ERK or Akt activation is required for the antiapoptotic effects of Gas6/Ark in GnRH neurons, cells were serum starved in the absence or presence of Gas6, with or without inhibitors of ERK and PI3-K signaling cascades. Gas6 rescued Gn10 cells from apoptosis, and this effect was blocked by coincubation of the cells with the mitogen-activated protein/ERK kinase (MEK) inhibitor, PD98059, or wortmannin (but not rapamycin). These data support an important role for Gas6/Ark signaling via the ERK and PI3-K (via Akt) pathways in the protection of GnRH neurons from programmed cell death across neuronal migration.

scholarly journals Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice

2011 ◽  
Vol 22 (10) ◽  
pp. 1766-1779 ◽  
Author(s):  
Karina Kaczmarek ◽  
Maja Studencka ◽  
Andreas Meinhardt ◽  
Krzysztof Wieczerzak ◽  
Sven Thoms ◽  
...  
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Germ Cells ◽  
Specific Gene ◽  
Male Mice ◽  
Terminal Part ◽  
Male Germ Cells ◽  
Germ Cell Apoptosis ◽  
Induced Apoptosis

 Peroxisomal testis-specific 1 gene (Pxt1) is the only male germ cell–specific gene that encodes a peroxisomal protein known to date. To elucidate the role of Pxt1 in spermatogenesis, we generated transgenic mice expressing a c-MYC-PXT1 fusion protein under the control of the PGK2 promoter. Overexpression of Pxt1 resulted in induction of male germ cells’ apoptosis mainly in primary spermatocytes, finally leading to male infertility. This prompted us to analyze the proapoptotic character of mouse PXT1, which harbors a BH3-like domain in the N-terminal part. In different cell lines, the overexpression of PXT1 also resulted in a dramatic increase of apoptosis, whereas the deletion of the BH3-like domain significantly reduced cell death events, thereby confirming that the domain is functional and essential for the proapoptotic activity of PXT1. Moreover, we demonstrated that PXT1 interacts with apoptosis regulator BAT3, which, if overexpressed, can protect cells from the PXT1-induced apoptosis. The PXT1-BAT3 association leads to PXT1 relocation from the cytoplasm to the nucleus. In summary, we demonstrated that PXT1 induces apoptosis via the BH3-like domain and that this process is inhibited by BAT3.

scholarly journals discs large regulates somatic cyst cell survival and expansion in Drosophila testis

Cell Research ◽  
2009 ◽  
Vol 19 (10) ◽  
pp. 1139-1149 ◽  
Author(s):  
Fani Papagiannouli ◽  
Bernard M Mechler
Keyword(s):  
Cell Survival ◽  
Cyst Cell ◽  
Discs Large ◽  
Drosophila Testis ◽  
Somatic Cyst Cell

Prevention of growth arrest-induced cell death of vascular smooth muscle cells by a product of growth arrest-specific gene, gas6

FEBS Letters ◽  
1996 ◽  
Vol 387 (1) ◽  
pp. 78-80 ◽  
Author(s):  
Toru Nakano ◽  
Keiko Kawamoto ◽  
Ken-ichi Higashino ◽  
Hitoshi Arita
Keyword(s):  
Cell Death ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Growth Arrest ◽  
Muscle Cells ◽  
Specific Gene

scholarly journals Polyunsaturated Fatty Acid (PUFA) Signaling Induces Ferroptosis-Mediated Cell-Death in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3108-3108
Author(s):  
Cristina Panaroni ◽  
Keertik Fulzele ◽  
Rosemary Soucy ◽  
Cherrie Huang ◽  
Kenta Mukaihara ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Multiple Myeloma ◽  
Cell Death ◽  
Fatty Acid ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Specific Gene ◽  
Myeloma Cells ◽  
Cox Inhibitor

Altered cellular metabolic pathways are the hallmark of tumor cells. Multiple myeloma (MM) is positively correlated with metabolic disorders such as obesity and Gaucher's disease. The local bone marrow (BM) microenvironment (TME) majorly influences the initiation and progression of MM. In a typical MM patient, BM adipocytes make up 70% of the cellular volume. The abundance of adipocyte-secreted free fatty acids (FFA) may shift myeloma cellular metabolism from aerobic glycolysis to more energy-producing fatty acid oxidation. The FFAs are important catalysts of key downstream drug-targetable signaling pathways such as cyclooxygenase (COX), cytochrome P450 (CYP), and lipoxygenase (LOX) pathways. In this study, we hypothesized that altered lipid profile in the local BM TME contributes to MM progression. BM-Fat enriched tissue isolated from BM aspirates of Monoclonal Gammopathy of Undetermined Significance (MGUS) and smoldering MM (SMM) patients showed a significant increase in adipogenic PPARγ gene expression compared to aged-matched healthy donors (N≥3). The BM mesenchymal stem/progenitor cells (BMSCs) from MGUS/SMM patients expressed normal levels of BMSC markers CD271, CD105, CD44, CD106, CD29, CD90, CD49e, and Notch4 but showed significantly increased expression of adipogenic markers including Preadipocyte factor 1, Leptin Receptor, and Perilipin A (N=6). This also translated into significantly increased adipogenic differentiation of patient BMSCs when cultured alone or with the human MM cell-line MM.1S (N≥3). Furthermore, MM.1S showed significantly increased proliferation when co-cultured with BMSCs from MGUS/SMM patients (N=5). These data demonstrate a vicious cycle where adipogenesis is increased in early precursor MM stages that further support the growth of myeloma cells. We performed gas chromatometry based lipidomics analysis on the supernatant of BM aspirates from MGUS, SMM, and newly diagnosed MM (NDMM) patients. The analysis identified significant decreases in key polyunsaturated fatty acids (PUFA) including Arachidonic Acid (AA) and Docosatetraenoic acid (N≥5). Lipid metabolism specific gene array on RNA from adipose tissue fraction of BM aspirates from MGUS, SMM and NDMM patients showed altered changes in genes responsible for fatty acid synthesis and metabolism. PUFA are involved in anti-inflammatory mechanisms in cancer. We hypothesized that increased levels of certain PUFA, such as AA, in the BM TME may decrease MM progression. To test this hypothesis, we treated MM cells with physiological doses of AA. AA dose-dependently decreased proliferation and viability of human MM cell lines, MM1S, H929, and U266, and CD138+ patient myeloma cells. For in vivo studies, humanized MM tumor model was generated in SCID mice by growing MM.1S cells in the intrascapular subcutaneous region for 3-weeks. Mice were then treated with daily localized injections of vehicle, 100µg/g AA, 500µg/g of AA, or IV with 2mg/kg/biweekly Carfilzomib (CFZ), or CFZ with 500µg/g of AA (COMBO). Tumor volume significantly decreased in 500µg/g AA treatment group beginning 10-days and was comparable to the CFZ treatment. Gross examination and flow cytometry analysis of CD138+ myeloma cells showed dramatically increased tumor-cell apoptosis in 500µg/g AA and COMBO treatment groups. To identify the primary apoptosis-inducing AA signaling pathway in MM cells, we used specific inhibitors of each of these signaling pathways including ibuprofen (Cox inhibitor), baicalein (12-LOX inhibitor), BW B70C (5,15-LOX inhibitor), 1-aminobenzotriazole (CYP450 inhibitor), and ferrostatin (Ferroptosis/lipid peroxidation inhibitor). Among these compounds, ferrostatin treatment completely rescued AA induced apoptosis in the human MM.1S cells. Ferroptotic cell death is the result of an accumulation of lipid peroxides which is generally prevented by the enzyme Glutathione peroxidase 4 (GPX4). We, therefore investigated the role of AA on GPX4 and found that all MM cell lines partially or completely lost the expression of GPX4 when exposed to AA and that this effect was completely prevented when cotreated with Ferrostatin. Taken together, we show that BM adipocytes promote myeloma cell proliferation at least in part through secreted FFAs. Therapeutically targeting members of this signaling pathway, such as ferroptosis, is a potential novel treatment strategy for MM especially in the MGUS and SMM stages. Disclosures Raje: Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

scholarly journals Extracellular pH and high concentration of potassium regulate the primary necrosis in the yeast Saccharomyces cerevisiae.

2021 ◽  
Author(s):  
Victoria Bidiuk ◽  
Alexander Alexandrov ◽  
Airat Valiakhmetov
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Death ◽  
Yeast Cell ◽  
Gene Mutations ◽  
Cellular Membrane ◽  
Extracellular Ph ◽  
Specific Gene ◽  
High Concentration ◽  
Yeast Saccharomyces Cerevisiae ◽  
Neutral Ph

Abstract Extracellular pH has a significant impact on the physiology of the yeast cell, but its role in cell death has not been thoroughly investigated. We studied the effect of extracellular pH on the development of primary necrosis in Saccharomyces cerevisiae yeast under two general conditions leading to cell death. The first is sugar induced cell death (SICD), and the second is death caused by several specific gene deletions, which have been recently identified in a systematic screen. It was shown that in both cases, primary necrosis is suppressed at neutral pH. SICD was also inhibited by the protonophore dinitrophenol (DNP) and 150 mM extracellular K+, with the latter condition also benefiting survival of cell dying due to gene mutations. Thus, we show that neutral pH can suppress different types of primary necrosis. We suggest that changes to the cellular membrane potential can play a central role in yeast cell death.

BCL6 Transcriptionally Reprograms the DLBCL Genome by Forming Distinct Biochemically Active Complexes on Genes Corresponding to Different Pathways.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2646-2646
Author(s):  
Jose M. Polo ◽  
Katerina Chatzi ◽  
Tania Dell’Oso ◽  
Paola Lev ◽  
Ari Melnick
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Chromatin Structure ◽  
Transcriptional Control ◽  
Target Genes ◽  
Biological Effects ◽  
Hematologic Malignancies ◽  
Specific Gene ◽  
Control Mechanisms ◽  
Biochemical Mechanisms

Abstract Aberrant gene expression is a hallmark of cancer, and so it is not surprising that the most common category of oncogenes and tumor suppressors involved in hematologic malignancies are transcription factors. These factors mediate their effects by nucleating biochemically active cofactor complexes to modify the chromatin structure of their respective target genes. BCL6 is a transcriptional repressor and the most commonly involved oncogene in diffuse large B-cell lymphomas. BCL6 represses genes by recruiting several corepressor complexes including SMRT, N-CoR, BCoR; all of which bind to BCL6 through its BTB domain. Each of these complexes has different biochemical functions (e.g. BCoR forms a polycomb complex vs. SMRT which forms an HDAC3 complex). Moreover, our preliminary data suggested that BCL6 uses different sets of corepressors to mediate distinct biological effects, possibly by using different biochemical mechanisms at specific sets of target genes. Therefore, we hypothesized that BCL6 regulates its target genes using different biochemical tools, allowing it to exquisitely fine tune gene expression and provide specific control mechanisms for different biological functions. In order to test this hypothesis we first identified the direct target genes of BCL6 SMRT, N-CoR and BCoR by ChIP-on-chip in DLBCL cells (Ly1 cells) in multiple replicates, and examined whether the overlapping sets of genes corresponded to different gene pathways. We used a 24,000 promoter microarray representing 1.5 KB of sequence for each gene. The results show reproducible binding of BCL6 at 940 promoters, While BCoR bound to 770, SMRT to 545 and N-CoR to 487 promoters respectively. BCL6 and BCoR overlapped at 400 genes, preferentially involved in involve in cell cycle, cell death chromatin structure, ubiquitin dependent process and chemotaxis. BCL6 and SMRT overlapped on 376 genes, involved in immune response, cell motility and also as BCOR cell death, while N-CoR and BCL6 overlapped on 100 genes including transcriptional control and cell death pathways. The overlap between BCoR and SMRT was at 200 genes, BCoR and N-CoR at 60 genes and SMRT and N-CoR at 85 genes. All three overlapped at 50 genes. We also examined whether these corepressors were associated with specific combinations of histone modifications including H3K9 acetylation, H3K9 methylation, H3K4 methylation, H3K27 methylation, H4K16 acetylation and H3K36 acetylation. Taken together, the data indicate that specific subsets of BCL6 target genes are dependent on distinct biochemical mechanisms, suggesting that additional layers of biochemical complexity govern formation of gene repression complexes in DLBCL cells and providing opportunities for highly specific therapeutic targeting of specific gene programs.

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