scholarly journals Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts

2000 ◽  
Vol 347 (2) ◽  
pp. 543 ◽  
Author(s):  
Qin M. CHEN ◽  
Juping LIU ◽  
Jessica B. MERRETT
Keyword(s):  
Cell Cycle ◽  
Human Fibroblasts ◽  
Growth Arrest ◽  
Normal Human

scholarly journals Role of p14ARF in Replicative and Induced Senescence of Human Fibroblasts

2001 ◽  
Vol 21 (20) ◽  
pp. 6748-6757 ◽  
Author(s):  
Wenyi Wei ◽  
Ruth M. Hemmer ◽  
John M. Sedivy
Keyword(s):  
Replicative Senescence ◽  
Human Fibroblasts ◽  
Growth Arrest ◽  
Fibroblast Cell ◽  
Cell Types ◽  
Major Pathway ◽  
Telomere Shortening ◽  
Normal Human ◽  
Cell Strains

ABSTRACT Following a proliferative phase of variable duration, most normal somatic cells enter a growth arrest state known as replicative senescence. In addition to telomere shortening, a variety of environmental insults and signaling imbalances can elicit phenotypes closely resembling senescence. We used p53−/− and p21−/− human fibroblast cell strains constructed by gene targeting to investigate the involvement of the Arf-Mdm2-p53-p21 pathway in natural as well as premature senescence states. We propose that in cell types that upregulate p21 during replicative exhaustion, such as normal human fibroblasts, p53, p21, and Rb act sequentially and constitute the major pathway for establishing growth arrest and that the telomere-initiated signal enters this pathway at the level of p53. Our results also revealed a number of significant differences between human and rodent fibroblasts in the regulation of senescence pathways.

Cell cycle arrest and aberration yield in normal human fibroblasts. I. Effects of X‐rays and 195 MeV u−1C ions

2004 ◽  
Vol 80 (9) ◽  
pp. 621-634 ◽  
Author(s):  
E. Nasonova ◽  
K. Füssel ◽  
S. Berger ◽  
E. Gudowska‐Nowak ◽  
S. Ritter
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Human Fibroblasts ◽  
X Rays ◽  
Cycle Arrest ◽  
Normal Human ◽  
Aberration Yield

scholarly journals Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1.

1996 ◽  
Vol 7 (1) ◽  
pp. 101-111 ◽  
Author(s):  
R M Böhmer ◽  
E Scharf ◽  
R K Assoian
Keyword(s):  
Cell Cycle ◽  
Cell Adhesion ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Human Fibroblasts ◽  
Cytochalasin D ◽  
Phase Cell ◽  
Dependent Part ◽  
Molecular Events ◽  
Normal Human

The proliferation of many nontransformed cells depends on cell adhesion. We report here that disrupting the cytoskeleton in normal human fibroblasts causes the same cell cycle phenotype that is observed after blocking cell adhesion: suspended cells and cytochalasin D-treated monolayers fail to progress through G1 despite normal mitogen-induced expression of c-myc mRNA. Midway between G0 and the beginning of S-phase, cell cycle progression becomes independent of adhesion and the cytoskeleton. At this stage, the cells are also mitogen independent. Molecular analyses showed that Rb hyperphosphorylation and the induction of cyclin D1 occur slightly earlier than the transition to cytoskeleton independence. Moreover, these molecular events are blocked by cytochalasin D. Overall, our data indicate the following: 1) anchorage and cytoskeletal integrity are required throughout the mitogen-dependent part of G1; 2) mitogens and the cytoskeleton jointly regulate the phosphorylation of Rb; and 3) this interdependence is manifest in the regulation of cyclin D1.

scholarly journals Cell cycle progression after cleavage failure

2004 ◽  
Vol 165 (5) ◽  
pp. 609-615 ◽  
Author(s):  
Yumi Uetake ◽  
Greenfield Sluder
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Human Fibroblasts ◽  
Human Cell Line ◽  
Cycle Progression ◽  
Binucleate Cells ◽  
Normal Human ◽  
Cleavage Failure

Failure of cells to cleave at the end of mitosis is dangerous to the organism because it immediately produces tetraploidy and centrosome amplification, which is thought to produce genetic imbalances. Using normal human and rat cells, we reexamined the basis for the attractive and increasingly accepted proposal that normal mammalian cells have a “tetraploidy checkpoint” that arrests binucleate cells in G1, thereby preventing their propagation. Using 10 μM cytochalasin to block cleavage, we confirm that most binucleate cells arrest in G1. However, when we use lower concentrations of cytochalasin, we find that binucleate cells undergo DNA synthesis and later proceed through mitosis in >80% of the cases for the hTERT-RPE1 human cell line, primary human fibroblasts, and the REF52 cell line. These observations provide a functional demonstration that the tetraploidy checkpoint does not exist in normal mammalian somatic cells.

scholarly journals Human Telomeres Maintain Their Overhang Length at Senescence

2005 ◽  
Vol 25 (6) ◽  
pp. 2158-2168 ◽  
Author(s):  
Weihang Chai ◽  
Jerry W. Shay ◽  
Woodring E. Wright
Keyword(s):  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Cultured Cells ◽  
Human Fibroblasts ◽  
Growth Arrest ◽  
Overhang Length ◽  
Normal Human ◽  
Molecular Signal ◽  
Population Doublings ◽  
Global Reduction

ABSTRACT Normal human cells in culture enter replicative senescence after a finite number of population doublings. The exact molecular mechanisms triggering the growth arrest are poorly understood. A recent report on the disappearance of the G-rich 3′ telomeric overhang in senescent cells led to the hypothesis that loss of the 3′ G-rich overhang is the molecular signal that triggers senescence. Here, we describe a quantitative assay to measure the length of the G-rich 3′ telomeric overhangs from cultured cells. Using both this assay and the conventional nondenaturing hybridization assay for measuring G-rich overhangs, we show that normal human fibroblasts can maintain their overhangs at senescence. Furthermore, cells do not lose their overhangs when they bypass senescence after the inactivation of p53 and Rb. We thus conclude that a global reduction in overhang length is not the molecular signal that triggers replicative senescence.

Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts

2000 ◽  
Vol 347 (2) ◽  
pp. 543-551 ◽  
Author(s):  
Qin M. CHEN ◽  
Juping LIU ◽  
Jessica B. MERRETT
Keyword(s):  
Cell Cycle ◽  
Caspase 3 ◽  
Human Fibroblasts ◽  
Growth Arrest ◽  
S Phase ◽  
Phase Cell ◽  
G1 Arrest ◽  
Apoptotic Cells ◽  
Early Passage ◽  
Bax Protein

Early-passage human diploid fibroblasts (HDFs) undergo senescence-like growth arrest in response to sublethal concentrations of H2O2 [Chen and Ames (1994) Proc. Natl. Acad. Sci. U.S.A. 95, 4130-4134]. We determine here whether H2O2 can cause apoptosis in HDFs and the molecular changes that differ between apoptosis and senescence-like growth arrest. When exponentially growing early-passage IMR-90 cells were treated for 2 h with 50-200 μM (or 0.25-1 pmol/cell) H2O2, a fraction of cells detached at 16-32 h after the treatment. The cells remaining attached were growth-arrested and developed features of senescence in 1 week. The detached cells showed caspase-3 activation and typical morphological changes associated with apoptosis. Caspase-3 activation was H2O2 dose-dependent and preceded nuclear condensation or plasma membrane leakage. Apoptotic cells were mainly distributed in the S-phase of the cell cycle, while growth-arrested cells exhibited predominantly G1- and G2/M-phase distributions. H2O2 pretreatment induced G1 arrest and prohibited induction of apoptosis by a subsequent H2O2 challenge. The p53 protein showed an average 6.1-fold elevation in apoptotic cells and a 3.5-fold elevation in growth-arrested cells. Reduction of p53 levels with human papillomavirus E6 protein prohibited the activation of caspase-3 and decreased the proportion of apoptotic cells. Growth-arrested cells had elevated p21, while p21 was absent in apoptotic cells. Bcl-2 was elevated in both growth-arrested and apoptotic cells. Finally, although the overall level of bax did not change in growth-arrested or apoptotic cells, the solubility of bax protein increased in apoptotic cells. Our data suggest that in contrast with growth-arrested cells, apoptotic cells show an S-phase cell cycle distribution, a higher degree of p53 elevation, an absence of p21 protein and increased solubility of bax protein.

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