scholarly journals Distinct Signaling Pathways Mediate Stimulation of Cell Cycle Progression and Prevention of Apoptotic Cell Death by Estrogen in Rat Pituitary Tumor PR1 Cells

2003 ◽  
Vol 14 (12) ◽  
pp. 5051-5059 ◽  
Author(s):  
Simona Caporali ◽  
Manami Imai ◽  
Lucia Altucci ◽  
Massimo Cancemi ◽  
Silvana Caristi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Death ◽  
Dna Synthesis ◽  
Cell Survival ◽  
Pituitary Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Rat Pituitary ◽  
Stimulation Of

Estrogens control cell growth and viability in target cells via an interplay of genomic and extragenomic pathways not yet elucidated. Here, we show evidence that cell proliferation and survival are differentially regulated by estrogen in rat pituitary tumor PR1 cells. Pico- to femtomolar concentrations of 17β-estradiol (E2) are sufficient to foster PR1 cell proliferation, whereas nanomolar concentrations of the same are needed to prevent cell death that occurs at a high rate in these cells in the absence of hormone. Activation of endogenous (PRL) or transfected estrogen-responsive genes occurs at the same, higher concentrations of E2 required to promote cell survival, whereas stimulation of cyclin D3 expression and DNA synthesis occur at lower E2 concentrations. Similarly, the pure antiestrogen ICI 182,780 inhibits estrogen response element-dependent trans-activation and cell death more effectively than cyclin-cdk activity, G1-S transition, or DNA synthesis rate. In antiestrogen-treated and/or estrogen-deprived cells, death is due predominantly to apoptosis. Estrogen-induced cell survival, but not E2-dependent cell cycle progression, can be prevented by an inhibitor of c-Src kinase or by blockade of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway. These data indicate the coexistence of two distinguishable estrogen signaling pathways in PR1 cells, characterized by different functions and sensitivity to hormones and antihormones.

scholarly journals Flavin Oxidase-Induced ROS Generation Modulates PKC Biphasic Effect of Resveratrol on Endothelial Cell Survival

Biomolecules ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 209 ◽  
Author(s):  
Anna Maria Posadino ◽  
Roberta Giordo ◽  
Annalisa Cossu ◽  
Gheyath K. Nasrallah ◽  
Abdullah Shaito ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Dna Synthesis ◽  
Cell Survival ◽  
Cellular Response ◽  
Cell Cycle Progression ◽  
Natural Antioxidants ◽  
Cycle Progression ◽  
Protein Levels ◽  
The Impact

Background: Dietary intake of natural antioxidants is thought to impart protection against oxidative-associated cardiovascular diseases. Despite many in vivo studies and clinical trials, this issue has not been conclusively resolved. Resveratrol (RES) is one of the most extensively studied dietary polyphenolic antioxidants. Paradoxically, we have previously demonstrated that high RES concentrations exert a pro-oxidant effect eventually elevating ROS levels leading to cell death. Here, we further elucidate the molecular determinants underpinning RES-induced oxidative cell death. Methods: Using human umbilical vein endothelial cells (HUVECs), the effect of increasing concentrations of RES on DNA synthesis and apoptosis was studied. In addition, mRNA and protein levels of cell survival or apoptosis genes, as well as protein kinase C (PKC) activity were determined. Results: While high concentrations of RES reduce PKC activity, inhibit DNA synthesis and induce apoptosis, low RES concentrations elicit an opposite effect. This biphasic concentration-dependent effect (BCDE) of RES on PKC activity is mirrored at the molecular level. Indeed, high RES concentrations upregulate the proapoptotic Bax, while downregulating the antiapoptotic Bcl-2, at both mRNA and protein levels. Similarly, high RES concentrations downregulate the cell cycle progression genes, c-myc, ornithine decarboxylase (ODC) and cyclin D1 protein levels, while low RES concentrations display an increasing trend. The BCDE of RES on PKC activity is abrogated by the ROS scavenger Tempol, indicating that this enzyme acts downstream of the RES-elicited ROS signaling. The RES-induced BCDE on HUVEC cell cycle machinery was also blunted by the flavin inhibitor diphenyleneiodonium (DPI), implicating flavin oxidase-generated ROS as the mechanistic link in the cellular response to different RES concentrations. Finally, PKC inhibition abrogates the BCDE elicited by RES on both cell cycle progression and pro-apoptotic gene expression in HUVECs, mechanistically implicating PKC in the cellular response to different RES concentrations. Conclusions: Our results provide new molecular insight into the impact of RES on endothelial function/dysfunction, further confirming that obtaining an optimal benefit of RES is concentration-dependent. Importantly, the BCDE of RES could explain why other studies failed to establish the cardio-protective effects mediated by natural antioxidants, thus providing a guide for future investigation looking at cardio-protection by natural antioxidants.

scholarly journals The jun and fos protein families are both required for cell cycle progression in fibroblasts.

1991 ◽  
Vol 11 (9) ◽  
pp. 4466-4472 ◽  
Author(s):  
K Kovary ◽  
R Bravo
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Dna Synthesis ◽  
Cell Cycle Progression ◽  
S Phase ◽  
3T3 Cells ◽  
Cycle Progression ◽  
Serum Stimulation ◽  
Fos Protein ◽  
Stimulation Of

The expression of different members of the Jun and Fos families of transcription factors is rapidly induced following serum stimulation of quiescent fibroblasts. To determine whether these proteins are required for cell cycle progression, we microinjected affinity-purified antibodies directed against c-Fos, FosB, Fra-1, c-Jun, JunB, and JunD, and antibodies that recognize either the Fos or the Jun family of proteins, into Swiss 3T3 cells and determined their effects in cell cycle progression by monitoring DNA synthesis. We found that microinjection of anti-Fos and anti-Jun family antibodies efficiently blocked the entrance to the S phase of serum-stimulated or asynchronously growing cells. However, the antibodies against single members of the Fos family only partially inhibited DNA synthesis. In contrast, all three Jun antibodies prevented DNA synthesis more effectively than did any of the anti-Fos antibodies.

Cyclin-Dependent Kinase Phosphorylation of RUNX1/AML1 on Three Sites Increases Trans-Activation Potency and Stimulates Cell Proliferation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3351-3351
Author(s):  
Alan D. Friedman ◽  
Linsheng Zhang ◽  
Florence Bernardin Fried
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Aspartic Acid ◽  
Cell Cycle Progression ◽  
Hematopoietic Cell ◽  
Cyclin D3 ◽  
Cycle Progression ◽  
Inhibition Of Proliferation ◽  
Cdk Phosphorylation ◽  
Stimulation Of

RUNX1/AML1 regulates lineage-specific genes during hematopoiesis and also stimulates G1 cell cycle progression. CBFβ-SMMHC or AML1-ETO dominantly inhibit RUNX1 and slow G1 progression in hematopoietic cell lines or in murine or human marrow progenitors, cdk4, cyclin D2, or c-Myc overcome inhibition of proliferation by these CBF oncoproteins, exogenous RUNX1 stimulates G1 progression, and stimulation of G1 via deletion of p16INK4a or expression of E7 cooperates with CBFβ-SMMHC or TEL-AML1 to induce acute leukemia in mice. Induction of cdk4 or cyclin D3 transcription may underlie stimulation of G1 progression by RUNX1. Remarkably, the C. elegans ortholog of RUNX1, RNT-1, also stimulates G1 progression and couples stem cell proliferation with differentiation. Not only does RUNX1 regulate cell cycle progression, but in addition RUNX1 levels increase as hematopoietic cells progress from G1 to S and from S to G2/M. Within RUNX1, S48, S303, and S424 fit the cdk phosphorylation consensus, (S/T)PX(R/K). Phosphorylation of RUNX1 by cyclin dependent kinases on serine 303 was shown to mediate destabilization of RUNX1 in G2/M. We now find that S48 and S424 are also phosphorylated by cdk1 or cdk6. S48, S303, or S424 phosphopeptide antiserum that we developed specifically recognized kinased GST-RUNX1 and interacted with RUNX1 expressed in 293T cells or in the Ba/F3 hematopoietic cell line. S48 phosphorylation of RUNX1 paralleled total RUNX1 levels during cell cycle progression, S303 was more effectively phosphorylated in G2/M, and S424 in G1. Single, double, and triple mutation to alanine or to the partially phosphomimetic aspartic acid progressively diminished or increased trans-activation, such that the tripleA mutant activated a RUNX1 reporter 5-fold less potently than the tripleD mutant. Aspartic acid does not perfectly mimic serine phosphorylation, as illustrated by the much greater affinity of our antisera for wild-type RUNX1 versus RUNX1(tripleD), suggesting that the biologic effect of RUNX1 cdk phosphorylation is even more significant. The p300 co-activator retained interaction with the tripleA variant. The tripleD RUNX1 mutant rescued Ba/F3 cells from inhibition of proliferation by CBFβ-SMMHC more effectively than the tripleA mutant. Cdk phosphorylation of RUNX1 on three sites increases its ability to active transcription and to stimulate proliferation, potentially coupling entry of stem/progenitors into cycle with induction of genes required for hematopoietic lineage progression, such as those encoding myeloperoxidase, neutrophil elastase, the M-CSF receptor, and PU.1.

scholarly journals High Glucose Concentration Alters Cell Proliferation Dynamics in Human Hepatoma Cells

1999 ◽  
Vol 18 (5) ◽  
pp. 297-306 ◽  
Author(s):  
Prathibha S. Rao ◽  
Beverly D. Lyn-Cook ◽  
Neil A. Littlefield ◽  
Harihara M. Mehendale
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Lactate Dehydrogenase ◽  
Dna Synthesis ◽  
High Glucose ◽  
Glucose Concentration ◽  
Cell Cycle Progression ◽  
Treated Group ◽  
High Glucose Concentration ◽  
Cycle Progression

The aim of this study was to develop an in vitro model to investigate the molecular mechanisms of glucose-induced inhibition of cell proliferation. HuH7 cells were grown in the presence or absence of glucose for 7 days and cell proliferation was stimulated by exposure to thioacetamide. Lactate dehydrogenase leakage and 3H-thymidine incorporation were used as indices of toxicity and DNA synthesis, respectively. Cell cycle progression and protooncogene expression was monitored by flow cytometry and slot-blot analyses. Toxicity caused by thioacetamide regressed with time in the presence of 11 mM glucose (control). However, in the presence of 28 mM glucose, sustained toxicity was evident as mirrored by lactate dehydrogenase leakage. Peak DNA synthesis noted at 48 hours in the thioacetamide-treated group (11 mM glucose) was significantly diminished in the presence of 28 mM glucose. Increased c-myc expression was observed as early as 30 minutes in the thioacetamide-treated group. When cells were exposed to 28 mM glucose, c-myc expression was delayed and diminished. Methylation profile studies revealed no appreciable changes, but c-myc was significantly amplified in the control, thioacetamide-, and in the presence of 28 mM of glucose-treated groups which correlated with mRNA changes in these groups. In the glucose-pretreated group (28 mM) significant amplification of the c-myc gene was observed at later time points but there was no change in the mRNA expression, indicating that the expression was delayed. This study shows that high glucose concentrations diminish DNA synthesis and cell cycle progression normally stimulated by thioacetamide. It is concluded that high glucose concentration causes cell cycle arrest via perturbation in protooncogene expression and hence the use of high glucose concentrations in therapy should be carefully examined in situations where postsurgical healing and healing after xenobiotic-induced injury are encountered.

Glucocorticoid Inhibition of 235-1 Rat Pituitary Tumor Cell Cycle Progression

Endocrine ◽  
2002 ◽  
Vol 17 (2) ◽  
pp. 119-128 ◽  
Author(s):  
Beverly C Delidow ◽  
Miranda Wang ◽  
Sonita V Bhamidipaty ◽  
Lynn D Black
Keyword(s):  
Cell Cycle ◽  
Tumor Cell ◽  
Pituitary Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Rat Pituitary ◽  
Pituitary Tumor Cell

The jun and fos protein families are both required for cell cycle progression in fibroblasts

1991 ◽  
Vol 11 (9) ◽  
pp. 4466-4472
Author(s):  
K Kovary ◽  
R Bravo
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Dna Synthesis ◽  
Cell Cycle Progression ◽  
S Phase ◽  
3T3 Cells ◽  
Cycle Progression ◽  
Serum Stimulation ◽  
Fos Protein ◽  
Stimulation Of

The expression of different members of the Jun and Fos families of transcription factors is rapidly induced following serum stimulation of quiescent fibroblasts. To determine whether these proteins are required for cell cycle progression, we microinjected affinity-purified antibodies directed against c-Fos, FosB, Fra-1, c-Jun, JunB, and JunD, and antibodies that recognize either the Fos or the Jun family of proteins, into Swiss 3T3 cells and determined their effects in cell cycle progression by monitoring DNA synthesis. We found that microinjection of anti-Fos and anti-Jun family antibodies efficiently blocked the entrance to the S phase of serum-stimulated or asynchronously growing cells. However, the antibodies against single members of the Fos family only partially inhibited DNA synthesis. In contrast, all three Jun antibodies prevented DNA synthesis more effectively than did any of the anti-Fos antibodies.

scholarly journals Inhibition of endothelial cell proliferation by platelet factor-4 involves a unique action on S phase progression.

1994 ◽  
Vol 127 (4) ◽  
pp. 1121-1127 ◽  
Author(s):  
S K Gupta ◽  
J P Singh
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Dna Synthesis ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Endothelial Cell Proliferation ◽  
Platelet Factor ◽  
Cycle Progression

Modulation of endothelial cell proliferation and cell cycle progression by the "chemokine" platelet factor-4 (PF-4) was investigated. PF-4 inhibited DNA synthesis, as well as proliferation of endothelial cells derived from large and small blood vessels. Inhibition by PF-4 was independent of the type and the concentration of stimuli used for the induction of endothelial cell proliferation. Inhibition of cell growth by PF-4 was reversible. The effects of PF-4 were antagonized by heparin. Cell cycle analysis using [3H]thymidine pulse labeling during traverse of synchronous cells from G0/G1 to S phase revealed that addition of PF-4 during G1 phase completely abolished the entry of cells into S phase. In addition, PF-4 also inhibited DNA synthesis in cells that were already in S phase. In exponentially growing cells, addition of PF-4 resulted in an accumulation of > 70% of the cells in early S phase, as determined by FACS (Becton-Dickinson Immunocytometry Systems, Mountain View, CA). In cells synchronized in S phase by hydroxyurea and then released, addition of PF-4 promptly blocked further progression of DNA synthesis. These results demonstrate that in G0/G1-arrested cells, PF-4 inhibited entry of endothelial cells into S phase. More strikingly, our studies have revealed a unique mode of endothelial cell growth inhibition whereby PF-4 effectively blocked cell cycle progression during S phase.

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