scholarly journals Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms.

1997 ◽  
Vol 17 (6) ◽  
pp. 3181-3193 ◽  
Author(s):  
I Rogatsky ◽  
J M Trowbridge ◽  
M J Garabedian
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Growth Arrest ◽  
Receptor Activation ◽  
Regulatory Mechanisms ◽  
Activation Domain ◽  
Transcriptional Activation Domain ◽  
Cycle Arrest ◽  
U2os Cells

Glucocorticoids inhibit proliferation of many cell types, but the events leading from the activated glucocorticoid receptor (GR) to growth arrest are not understood. Ectopic expression and activation of GR in human osteosarcoma cell lines U2OS and SAOS2, which lack endogenous receptors, result in a G1 cell cycle arrest. GR activation in U2OS cells represses expression of the cyclin-dependent kinases (CDKs) CDK4 and CDK6 as well as their regulatory partner, cyclin D3, leading to hypophosphorylation of the retinoblastoma protein (Rb). We also demonstrate a ligand-dependent reduction in the expression of E2F-1 and c-Myc, transcription factors involved in the G1-to-S-phase transition. Mitogen-activated protein kinase, CDK2, cyclin E, and the CDK inhibitors (CDIs) p27 and p21 are unaffected by receptor activation in U2OS cells. The receptor's N-terminal transcriptional activation domain is not required for growth arrest in U2OS cells. In Rb-deficient SAOS2 cells, however, the expression of p27 and p21 is induced upon receptor activation. Remarkably, in SAOS2 cells that express a GR deletion derivative lacking the N-terminal transcriptional activation domain, induction of CDI expression is abolished and the cells fail to undergo ligand-dependent cell cycle arrest. Similarly, murine S49 lymphoma cells, which, like SAOS2 cells, lack Rb, require the N-terminal activation domain for growth arrest and induce CDI expression upon GR activation. These cell-type-specific differences in receptor domains and cellular targets linking GR activation to cell cycle machinery suggest two distinct regulatory mechanisms of GR-mediated cell cycle arrest: one involving transcriptional repression of G1 cyclins and CDKs and the other involving enhanced transcription of CDIs by the activated receptor.

scholarly journals A trans-Activation Domain in Yeast Heat Shock Transcription Factor Is Essential for Cell Cycle Progression during Stress

1999 ◽  
Vol 19 (1) ◽  
pp. 402-411 ◽  
Author(s):  
Kevin A. Morano ◽  
Nicholas Santoro ◽  
Keith A. Koch ◽  
Dennis J. Thiele
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Heat Shock ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Heat Shock Transcription Factor ◽  
Yeast Cells ◽  
Activation Domain ◽  
Cycle Arrest ◽  
Carboxyl Terminal

ABSTRACT Gene expression in response to heat shock is mediated by the heat shock transcription factor (HSF), which in yeast harbors both amino- and carboxyl-terminal transcriptional activation domains. Yeast cells bearing a truncated form of HSF in which the carboxyl-terminal transcriptional activation domain has been deleted [HSF(1-583)] are temperature sensitive for growth at 37°C, demonstrating a requirement for this domain for sustained viability during thermal stress. Here we demonstrate that HSF(1-583) cells undergo reversible cell cycle arrest at 37°C in the G2/M phase of the cell cycle and exhibit marked reduction in levels of the molecular chaperone Hsp90. As in higher eukaryotes, yeast possesses two nearly identical isoforms of Hsp90: one constitutively expressed and one highly heat inducible. When expressed at physiological levels in HSF(1-583) cells, the inducible Hsp90 isoform encoded by HSP82 more efficiently suppressed the temperature sensitivity of this strain than the constitutively expressed gene HSC82, suggesting that different functional roles may exist for these chaperones. Consistent with a defect in Hsp90 production, HSF(1-583) cells also exhibited hypersensitivity to the Hsp90-binding ansamycin antibiotic geldanamycin. Depletion of Hsp90 from yeast cells wild type for HSF results in cell cycle arrest in both G1/S and G2/M phases, suggesting a complex requirement for chaperone function in mitotic division during stress.

scholarly journals Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F

2015 ◽  
Vol 95 (6) ◽  
pp. 648-659 ◽  
Author(s):  
Amanda R Oliveira ◽  
Georg Beyer ◽  
Rohit Chugh ◽  
Steven J Skube ◽  
Kaustav Majumder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Cycle Arrest

scholarly journals Hypoxia-Inducible Factor 1α Is Essential for Cell Cycle Arrest during Hypoxia

2003 ◽  
Vol 23 (1) ◽  
pp. 359-369 ◽  
Author(s):  
Nobuhito Goda ◽  
Heather E. Ryan ◽  
Bahram Khadivi ◽  
Wayne McNulty ◽  
Robert C. Rickert ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Growth Arrest ◽  
Cell Types ◽  
Low Oxygen ◽  
Double Knockout ◽  
Cycle Arrest

ABSTRACT A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1α gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1α influenced p53, we also created double-knockout (HIF-1α null, p53 null) strains and cells. In both cell types, loss of HIF-1α abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1α genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition, we have found that the loss of HIF-1α causes an increased progression into S phase during hypoxia, rather than a growth arrest. We show that hypoxia causes a HIF-1α-dependent increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27; we also find that hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1α dependent. These data demonstrate that the transcription factor HIF-1 is a major regulator of cell cycle arrest in primary cells during hypoxia.

scholarly journals Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function.

1996 ◽  
Vol 16 (9) ◽  
pp. 4952-4960 ◽  
Author(s):  
R L Ludwig ◽  
S Bates ◽  
K H Vousden
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Sequences ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cycle Arrest ◽  
P53 Tumor Suppressor Protein

The p53 tumor suppressor protein is a sequence-specific transcriptional activator, a function which contributes to cell cycle arrest and apoptosis induced by p53 in appropriate cell types. Analysis of a series of p53 point mutants has revealed the potential for selective loss of the ability to transactivate some, but not all, cellular p53-responsive promoters. p53 175P and p53 181L are tumor-derived p53 point mutants which were previously characterized as transcriptionally active. Both mutants retained the ability to activate expression of the cyclin-dependent kinase inhibitor p2lcip1/waf1, and this activity correlated with the ability to induce a G1 cell cycle arrest. However, an extension of this survey to include other p53 targets showed that p53 175P was defective in the activation of p53-responsive sequences derived from the bax promoter and the insulin-like growth factor-binding protein 3 gene (IGF-BP3) promoter, while p53 181L showed loss of the ability to activate a promoter containing IGF-BP3 box B sequences. Failure to activate transcription was also reflected in the reduced ability of the mutants to bind the p53-responsive DNA sequences present in these promoters. These specific defects in transcriptional activation correlated with the impaired apoptotic function displayed by these mutants, and the results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response. The cellular response to p53 activation may therefore depend, at least in part, on which group of p53-responsive genes become transcriptionally activated.

scholarly journals Sonic Hedgehog Opposes Epithelial Cell Cycle Arrest

1999 ◽  
Vol 147 (1) ◽  
pp. 71-76 ◽  
Author(s):  
Hongran Fan ◽  
Paul A. Khavari
Keyword(s):  
Cell Cycle ◽  
Epithelial Cell ◽  
Cell Cycle Arrest ◽  
Sonic Hedgehog ◽  
Growth Arrest ◽  
Epidermal Hyperplasia ◽  
Shh Pathway ◽  
Cycle Arrest ◽  
Pathway Activation

Stratified epithelium displays an equilibrium between proliferation and cell cycle arrest, a balance that is disrupted in basal cell carcinoma (BCC). Sonic hedgehog (Shh) pathway activation appears sufficient to induce BCC, however, the way it does so is unknown. Shh-induced epidermal hyperplasia is accompanied by continued cell proliferation in normally growth arrested suprabasal cells in vivo. Shh-expressing cells fail to exit S and G2/M phases in response to calcium-induced differentiation and also resist exhaustion of replicative growth capacity. In addition, Shh blocks p21CIP1/WAF1-induced growth arrest. These data indicate that Shh promotes neoplasia by opposing normal stimuli for epithelial cell cycle arrest.

scholarly journals Ste12 and Mcm1 regulate cell cycle-dependent transcription of FAR1.

1996 ◽  
Vol 16 (6) ◽  
pp. 2830-2837 ◽  
Author(s):  
L J Oehlen ◽  
J D McKinney ◽  
F R Cross
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcriptional Activation ◽  
G1 Phase ◽  
Protein Accumulation ◽  
Transcriptional Activation Domain ◽  
Cycle Arrest ◽  
Gal1 Promoter ◽  
Combinatorial Control ◽  
Cycle Dependent

The transcripts of many genes involved in Saccharomyces cerevisiae mating were found to fluctuate during the cell cycle. In the absence of a functional Ste12 transcription factor, both the levels and the cell cycle pattern of expression of these genes were affected. FUS1 and AGA1 levels, which are maximally expressed only in G1-phase cells, were strongly reduced in ste12- cells. The cell cycle transcription pattern for FAR1 was changed in ste12- cells: the gene was still significantly expressed in G2/M, but transcript levels were strongly reduced in G1 phase, resulting in a lack of Far1 protein accumulation. G2/M transcription of FAR1 was dependent on the transcription factor Mcm1, and expression of a gene with Mcm1 fused to a strong transcriptional activation domain resulted in increased levels of FAR1 transcription. The pattern of cell cycle-regulated transcription of FAR1 could involve combinatorial control of Ste12 and Mcm1. Forced G1 expression of FAR1 from the GAL1 promoter resorted the ability to arrest in response to pheromone in ste12-cells. This indicates that transcription of FAR1 in the G1 phase is essential for accumulation of the protein and for pheromone-induced cell cycle arrest.

A novel nucleolar protein, PAPA-1, induces growth arrest as a result of cell cycle arrest at the G1 phase

Gene ◽  
2004 ◽  
Vol 340 (1) ◽  
pp. 83-98 ◽  
Author(s):  
Taruho S. Kuroda ◽  
Hiroshi Maita ◽  
Takanori Tabata ◽  
Takahiro Taira ◽  
Hirotake Kitaura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Growth Arrest ◽  
Nucleolar Protein ◽  
G1 Phase ◽  
Cycle Arrest

scholarly journals Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN

2000 ◽  
Vol 20 (23) ◽  
pp. 8969-8982 ◽  
Author(s):  
Noriaki Nakamura ◽  
Shivapriya Ramaswamy ◽  
Francisca Vazquez ◽  
Sabina Signoretti ◽  
Massimo Loda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Active Form ◽  
Forkhead Transcription Factors ◽  
Cycle Arrest ◽  
In Cells ◽  
Constitutively Active

ABSTRACT PTEN acts as a tumor suppressor, at least in part, by antagonizing phosphoinositide 3-kinase (PI3K)/Akt signaling. Here we show that Forkhead transcription factors FKHRL1 and FKHR, substrates of the Akt kinase, are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells. Restoration of PTEN function restores FKHR to the nucleus and restores transcriptional activation. Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells. Specifically, activated FKHR induces apoptosis in cells that undergo PTEN-mediated cell death and induces G1 arrest in cells that undergo PTEN-mediated cell cycle arrest. Furthermore, both PTEN and constitutively active FKHR induce p27KIP1 protein but not p21. These data suggest that Forkhead transcription factors are critical effectors of PTEN-mediated tumor suppression.

scholarly journals Transcriptional activation of Odf2/Cenexin by cell cycle arrest and the stress activated signaling pathway (JNK pathway)

2013 ◽  
Vol 1833 (6) ◽  
pp. 1338-1346 ◽  
Author(s):  
Nadin Pletz ◽  
Anja Medack ◽  
Eva Maria Rieß ◽  
Kefei Yang ◽  
Zahra Basir Kazerouni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Jnk Pathway ◽  
Cycle Arrest

DNA damage–induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 834-841 ◽  
Author(s):  
Matthew K. Henry ◽  
Jeffrey T. Lynch ◽  
Alex K. Eapen ◽  
Frederick W. Quelle
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Growth Arrest ◽  
Hematopoietic Cells ◽  
Akt Signaling ◽  
Dominant Negative ◽  
Akt Signaling Pathway ◽  
Cycle Arrest

Abstract Exposure of hematopoietic cells to DNA-damaging agents induces cell-cycle arrest at G1 and G2/M checkpoints. Previously, it was shown that DNA damage–induced growth arrest of hematopoietic cells can be overridden by treatment with cytokine growth factors, such as erythropoietin (EPO) or interleukin-3 (IL-3). Here, the cytokine-activated signaling pathways required to override G1 and G2/M checkpoints induced by γ-irradiation (γ-IR) are characterized. Using factor-dependent myeloid cells stably expressing EPO receptor (EPO-R) mutants, it is shown that removal of a minimal domain required for PI-3K signaling abrogated the ability of EPO to override γ-IR–induced cell-cycle arrest. Similarly, the ability of cytokines to override γ-IR–induced arrest was abolished by an inhibitor of PI-3K (LY294002) or by overexpression of dominant-negative Akt. Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt. Thus, activation of a PI-3K/Akt signaling pathway is required for cytokine-dependent suppression of DNA-damage induced checkpoints. Together, these findings suggest a novel role for PI-3K/Akt pathways in the modulation of growth arrest responses to DNA damage in hematopoietic cells.

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