Gamma irradiation leads to two waves of apoptosis in distinct cell populations of the retina of newborn rats

1999 ◽  
Vol 112 (23) ◽  
pp. 4315-4324
Author(s):  
H.L. Borges ◽  
R. Linden
Keyword(s):  
Cell Cycle ◽  
Gamma Irradiation ◽  
Chromatin Condensation ◽  
S Phase ◽  
Cell Populations ◽  
Apoptotic Cells ◽  
Rat Retina ◽  
Proliferative Zone ◽  
Distinct Cell ◽  
Late Wave

Gamma radiation induces apoptosis in the proliferative zone (neuroblastic layer) of the developing rat retina. We asked whether sensitivity to apoptosis might be related to distinct phases of the cell cycle. Explants of newborn rat retina or newborn pups were gamma-irradiated and apoptosis was detected by chromatin condensation, DNA fragmentation in situ and DNA electrophoresis. After 6 hours, early appearing apoptotic bodies were located mainly towards the outer tier of the neuroblastic layer. In contrast, after 24 hours, late-appearing apoptotic cells were located towards the inner margin of the neuroblastic layer, a region associated with the S phase of the cell cycle. Labeling of a cohort of cells with the nucleotide analog bromo-deoxyuridine (BrdU) at the time of irradiation, showed that these cells die in the late wave of apoptosis. BrdU given 3 hours before fixation labeled a large number of late apoptotic cells, but no early apoptotic cells. After labeling of all cycling cells with BrdU, 40% of the early apoptotic profiles were unlabeled, and thus post-mitotic. The same schedules of cell death were identified after gamma irradiation in vivo. The results show that irradiation leads to two waves of apoptosis in distinct cell populations. An early wave comprises both post-mitotic cells and proliferating cells out of the S phase. The late wave comprises cells in S phase, which pass through this phase again to die. The antioxidant pyrrolidinedithiocarbamate prevented the early but not the late wave of apoptosis following irradiation, and blocked lipid peroxidation at 6 hours after the insult, suggesting that the two waves of apoptosis are indeed mediated by distinct mechanisms.

Resistance to Apoptosis and Cell Proliferation in the hCG-PMl-RARα Transgenic Mouse Model Are Age-Related.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2757-2757
Author(s):  
Priscila S. Scheucher ◽  
Barbara A.A. Santana ◽  
Rodrigo S. Abreu e Lima ◽  
Guilherme A.S. Santos ◽  
Aglair B. Garcia ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
S Phase ◽  
Apoptotic Cells ◽  
Γ Irradiation ◽  
Age Related ◽  
Significant Difference ◽  
Tm Model ◽  
Leukemic Phase

Abstract Acute promyelocytic leukemia (APL) is associated with the t(15;17) which generates the PML-RARa fusion gene. The encoded PML-RARα oncoprotein physically interacts with native PML impairing its function. PML is a potent inhibitor of proliferation and apoptosis. In addition, mouse embryonic fibroblasts in which PML was inactivated (PML−/− MEFs) exhibit a significant increase in the percentage (%) of cells in S phase accompanied by the decrease in the G0/G1 subpopulation. Transgenic mice (TM) hCG-PML-RARα develop a form of leukemia similar to human APL after a long period of latency, suggesting that PML-RARα expression is necessary but not sufficient to leukemogenesis. Leukemic cells of the TM model present increased proliferation associated with resistance of apoptosis. Nevertheless, it is not known whether these changes are present from birth and thus related to exclusively to PML/RARα expression, or appear late in life and are associated with additional mutagenic events. To address this issue, we have analyzed TM of different ages without hematological abnormalities. We characterized the distribution of cells in the phases of cell cycle, cell proliferation and resistance to apoptosis in vivo. Cell cycle was analyzed in bone marrow (BM) cells stained with propidium iodate (PI) and analyzed by flow cytometry (FC). In TM younger than 9m (n=12), there was no significant difference in cell cycle distribution compared to wild-type (WT) controls. In contrast, in TM older than 9m (n=15) the % of BM cells in S phase was significantly lower (TM=14,84 ± 3,39%; WT=18,26 ± 3,55%; p=0,005) and was associated with increase in the % of cells in G0/G1 (TM=81,69 ± 3,79%; WT=78,14 ± 3,70%; p=0,001). The proliferation was tested in vivo by injecting bromodeoxyuridine i.p. and assessing its incorporation by BM cells after 2h. Compared to WT controls, there was a significantly lower % of proliferating cells in TM older than 9m (19,48 ± 7,81 versus 23,20 ± 10,80% in WT; p=0,06). Apoptosis was induced by γ irradiation, and after 24h BM cells were obtained and stained with PI. The % of apoptotic cells was determined by quantifying sub-G0 peak by FC. BM cells from TM older than 9m, but not from younger mice, were resistant to apoptosis. In this age group, γ-irradiation induced a 2,24 ± 0,81-fold increase in the % of apoptotic cells, whereas in WT controls this increase was of 4,06 ± 3,01-fold (p=0,018). Finally, in order to analyze the transcriptional mechanisms subjacent to the resistance, we measured the expression of two candidate genes involved in cell cycle and apoptosis regulation: p21Waf1/Cip1 and CDKN2A. The analysis was restricted to myeloid precursors by isolating CD117+ cells through an immunomagnetic technique. We found that both p21Waf1/Cip1 and CDKN2A are up-regulated in TM older than 9m. Moreover, this up-regulation was detected in both irradiated and unirradiated TM. Our results showed that resistance to apoptosis is associated with a block of the transition G1/S in the pre-leukemic phase of hCG-PML-RARα TM model, in contrast with the previously demonstrated increase in proliferation and resistance to apoptosis in the leukemic phase. Therefore deregulation of cell cycle is a late event during APL genesis and may be associated with additional mutagenic events.

scholarly journals Heat shock results in cell cycle delay and synchronisation of mitotic domains in cellularised Drosophila melanogaster embryos

1993 ◽  
Vol 105 (3) ◽  
pp. 711-720 ◽  
Author(s):  
G. Maldonado-Codina ◽  
S. Llamazares ◽  
D.M. Glover
Keyword(s):  
Cell Cycle ◽  
Heat Shock ◽  
Chromatin Condensation ◽  
Cell Cycle Control ◽  
S Phase ◽  
Temperature Shock ◽  
Cell Cycle Delay ◽  
Minute Period ◽  
G2 Phase ◽  
Drosophila Embryos

Cells of Drosophila embryos that are subjected to a 37 degrees C temperature shock whilst undergoing the S-phase of cell cycle 14 arrest with their microtubules in an interphase-like state, and with nuclei showing unusual chromatin condensation. They do not recover from this state within a 30 minute period even though extensive gastrulation movements can occur. Cells of embryos heat shocked in G2-phase are delayed in interphase with high levels of cyclins A and B. Within ten minutes recovery from heat shock, cells enter mitosis throughout the embryo. The degradation of the mitotic cyclins A and B in these synchronised mitotic domains does not follow the normal timing, but is delayed. These findings point to a need for caution when interpreting experiments that use the heat shock promoter to study the expression of cell cycle control genes in Drosophila.

Mass Cytometric Analysis of AML Stem and Early Progenitor Cells Reveals Karyotype and Genotype-Specific Cell Cycle Properties That Correlate with Known Responses to Chemotherapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2359-2359
Author(s):  
Gregory K. Behbehani ◽  
Wendy J. Fantl ◽  
Bruno C Medeiros ◽  
Garry P. Nolan
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
S Phase ◽  
The Other ◽  
Cytotoxic Agents ◽  
Phase Fraction ◽  
Cell Populations

Abstract Introduction: Leukemic stem cells (LSCs) are recognized as important mediators of chemotherapy resistance and leukemia relapse. The postulated mechanism for this is the relative quiescence of these cell populations that renders them resistant to cytotoxic agents. This simple hypothesis, however, is supported almost entirely by indirect evidence, and fails to explain the large differences in relapse rates across different AML subtypes. To address this question, we have developed a mass cytometry (MCM) approach to assess the cell cycle of immunophenotypically complex primary samples from patients with AML. By processing samples immediately upon bone marrow harvest, we could determine if AML stem cells were quiescent in vivo and if the cell cycle properties of these cells varied between chemotherapy-responsive versus resistant AML subtypes. Methods: Bone marrow aspirates from 33 AML patients, 3 with APL, 2 with high-risk MDS, 5 with AML who achieved a CR with chemotherapy treatment, and 5 healthy donors (48 total samples) were incubated at 37°C for 15 minutes with 20uM Iodo-deoxyuridine (IdU) immediately after aspiration (<1 min), followed by fixation and storage. Samples were then analyzed with two overlapping 39-antibody MCM panels (50 markers total). Cellular barcoding was utilized to stain and analyze cells in tubes of 20 samples each, enabling direct comparison of samples to each other and to the healthy controls. Results: The high dimensionality of MCM enabled the simultaneous measurement of 25 surface markers and the identification of almost all immunophenotypic populations in human bone marrow. The use of barcoding, and the resultant ability to directly compare samples, enabled the detection of aberrant marker expression at very high resolution (2-3 fold changes). At least one surface marker aberrancy was detected in each AML sample. Unexpectedly, cell cycle analysis revealed that, compared to immunophenotypically similar normal cells, the average fraction of S-phase cells in AML samples was significantly lower. In both AML and healthy samples, the lowest S-phase fraction was found in fully differentiated populations and in hematopoietic stem cells (HSCs) while committed progenitor populations (myelo-monoblasts, promyelocytes, erythroblasts) exhibited the highest S-phase fraction. The HSC and early progenitor cell populations from patients with CBF AML (t(8;21) and inv(16)) demonstrated a significantly higher S-phase fraction than the same cell populations from the other AML samples (7.76% vs. 2.66%; p=0.0014). Furthermore, samples with FLT3-ITD mutations exhibited the lowest S-phase fraction in the HSC and early progenitor cell populations (0.63%), which was significantly lower than the S-phase fraction of the other AML samples (4.37%; p=9.3x10-4). Finally, a subset of patients (n=10) was being treated with hydroxyurea (HU) at the time of their bone marrow aspiration. The effect of HU treatment was manifest as a reduction in the IdU incorporation rate (with no change in S-phase fraction) in the cells of the treated patients. However, neither cell cycle arrest nor apoptosis were observed in these samples. This is in contrast with the commonly observed occurrence of both in leukemic cell lines treated in vitro with HU. Conclusions: By combining fresh sample processing with high-dimensional MCM analysis, we developed an innovative approach for the analysis of hematologic malignancies. Our results suggest that the relative sensitivity of CBF AML to cytotoxic chemotherapy may be the result of the increased fraction of S-phase cells within the HSC and early progenitor cell populations. Conversely, HSC and early progenitor cell populations from patients with FLT3-ITD mutations would be expected to be particularly resistant to cytarabine-based consolidation therapy due to the very low frequency of S-phase cells within these populations. This finding, combined with our observation that the stem and early progenitor cells from the FLT3-ITD samples have high expression of CD33, may provide a mechanistic explanation for the improved disease-free survival recently reported for FLT3-ITD AML patients treated with fractioned gemtuzumab ozogamicin in combination with standard therapy. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Behbehani: Fluidigm: Consultancy. Medeiros:Agios: Consulting - Ad board Other. Nolan:Fluidigm, Inc: Consultancy, Equity Ownership.

scholarly journals Lymphocyte cell-cycle analysis by flow cytometry. Evidence for a specific postmitotic phase before return to G0.

1980 ◽  
Vol 85 (2) ◽  
pp. 459-465 ◽  
Author(s):  
D P Richman
Keyword(s):  
Cell Cycle ◽  
Human Lymphocytes ◽  
Late Phase ◽  
S Phase ◽  
Cycle Phase ◽  
Thymidine Uptake ◽  
Large Numbers ◽  
Distinct Cell ◽  
Lymphocyte Cell ◽  
Supravital Staining

We studied the cell cycle of lectin-stimulated human lymphocytes, making use of a flow cytometer. The RNA and DNA content of large numbers of individual cells was determined by supravital staining with acridine orange. The present study confirmed previous observations by others of a progression from G0 through G1 and S phase to G2/mitosis during the first 3 d in culture. It was also found that on subsequent days stimulated cells, before their return to G0, remained stationary in a state in which they contained the G0 complement of DNA and approximately twice the G0 complement of RNA. Cell-cycle manipulation with vinblastine and 5-bromo-2-deoxyuridine (BUdR) revealed that previous passage through both S phase and mitosis was required for entry into this newly observed late phase. In addition, there was high correlation (r = 0.973, P less than 0.001) between the number of cells in the late phase and measured [3H]thymidine uptake. It therefore appears that, in this system, stimulated cells remain in a distinct cell-cycle phase for a number of hours before their return to the resting state.

scholarly journals Distinct cell cycle–dependent roles for dynactin and dynein at centrosomes

2002 ◽  
Vol 159 (2) ◽  
pp. 245-254 ◽  
Author(s):  
Nicholas J. Quintyne ◽  
Trina A. Schroer
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Centrosome Duplication ◽  
Cell Cycle Regulators ◽  
Cycle Progression ◽  
Microtubule Array ◽  
Delayed Entry ◽  
Distinct Cell ◽  
Cycle Dependent

Centrosomal dynactin is required for normal microtubule anchoring and/or focusing independently of dynein. Dynactin is present at centrosomes throughout interphase, but dynein accumulates only during S and G2 phases. Blocking dynein-based motility prevents recruitment of dynactin and dynein to centrosomes and destabilizes both centrosomes and the microtubule array, interfering with cell cycle progression during mitosis. Destabilization of the centrosomal pool of dynactin does not inhibit dynein-based motility or dynein recruitment to centrosomes, but instead causes abnormal G1 centriole separation and delayed entry into S phase. The correct balance of centrosome-associated dynactin subunits is apparently important for satisfaction of the cell cycle mechanism that monitors centrosome integrity before centrosome duplication and ultimately governs the G1 to S transition. Our results suggest that, in addition to functioning as a microtubule anchor, dynactin contributes to the recruitment of important cell cycle regulators to centrosomes.

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.

scholarly journals The Essential Cell Cycle Regulator Setd8 Drives Chromatin Condensation during Terminal Erythroid Maturation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1035-1035
Author(s):  
Jeffrey Malik ◽  
Jacquelyn Lillis ◽  
Michael Getman ◽  
Laurie A Steiner
Keyword(s):  
Cell Cycle ◽  
Chromatin Structure ◽  
Cell Cycle Progression ◽  
Chromatin Condensation ◽  
Higher Order ◽  
S Phase ◽  
Cycle Progression ◽  
Cell Cycle Regulator ◽  
The Impact ◽  
Mitotic Chromatin

Abstract Chromatin condensation culminating in enucleation is a hallmark of erythropoiesis, however the mechanisms driving this process are incompletely understood. Setd8 is the sole enzyme that can mono-methylate histone H4, lysine 20 (H4K20me1) and is an important regulator of cell cycle progression, higher order chromatin structure, and genome stability. (Reviewed in Beck, Genes and Development, 2010) Setd8 and H4K20me1 are unique among epigenetic regulators in that their expression is dynamically regulated during the cell cycle. Setd8 expression peaks during G2/M, where it promotes mitotic chromatin condensation, and becomes undetectable during S-phase due to ubiquitin dependent destruction. (Oda, Mol Cell, 2010) The presence of H4K20me1 mirrors that of Setd8, peaking in G2/M, and reaching a nadir during S-phase due to removal by the histone demethylase PHF8. (Liu, Nature, 2010) Interestingly, Setd8 is expressed at levels 8- to 10- fold higher in CD71+ erythroblasts than in any other cell type, (Wu Genome Biology,2009) suggesting that it has an erythroid-specific function. We hypothesize that Setd8 drives chromatin condensation in maturing erythroblasts. In cell lines, forced accumulation of H4K20me1 during S-phase due to perturbation of either Setd8 or PHF8 results in pre-mitotic chromatin condensation (Centore Mol Cell 2010; Liu Nature 2010). We demonstrate that primary erythroblasts express Setd8 and accumulate H4K20me1 throughout the cell cycle, suggesting that Setd8 and H4K20me1 in promote chromatin condensation during terminal maturation. We further demonstrate that Setd8 is essential for erythropoiesis, with erythroid-specific Setd8 deletion resulting in profound anemia that is lethal by E12.5. The early onset of anemia indicates a defect in the primitive erythroid lineage, which emerges from the yolk sac at E8.5, and proliferates, matures, and enucleates in the circulation as a semi-synchronous cohort. (Kingsley, Blood, 2004) Detailed analyses of Setd8-null erythroblasts revealed severe defects in cell cycle progression, increased DNA content suggesting loss of genomic integrity, accumulation of DNA damage, and a modest increase in the rate of apoptosis. Global transcriptome analyses demonstrated that Setd8-null erythroblasts had activation of checkpoint genes such as CDKN1a and Gene Set Enrichment Analyses identified significant enrichment of cell cycle and p53 signaling pathways. Despite evidence of p53 activation, concomitant p53 deletion was not able to rescue the Set8-null phenotype, indicating that Setd8 has an essential role in promoting erythroid proliferation and survival that is independent of the p53 pathway. Consistent with our hypothesis that Setd8 drives chromatin condensation in maturing erythroblasts, the nuclear area of Setd8-null cells was nearly twice that of controls at E11.5 (119 and 69 um2, respectively p<0.0003). Transmission electron microscopy confirmed a profound defect in global chromatin condensation in the Setd8-null cells. Unexpectedly, heterochromatin was nearly absent from the Setd8-null cells, with the Setd8-null cells containing only a small amount of heterochromatin localized to the nuclear periphery. To determine the impact of Setd8 deletion on local chromatin structure, we performed ATAC-seq (Assay for Transposase Accessible Chromatin) on sorted populations of Setd8-null and control erythroblasts. Preliminary analyses of ATAC-seq data identified 364 ATAC peaks present in the Setd8-null cells but not in controls (p<0.001). Intriguingly, Gene Ontogeny analyses of the genes nearest to those regions was significant for multiple terms associated with higher order chromatin structure including "regulation of chromatin organization" and "positive regulation of histone deacetylation." Taken together, our results indicate that erythroblasts have adapted an essential cell cycle regulator to drive chromatin condensation during terminal maturation. Disclosures No relevant conflicts of interest to declare.

Rhein Induces Apoptosis and Cell Cycle Arrest in Human Hepatocellular Carcinoma BEL-7402 Cells

2008 ◽  
Vol 36 (04) ◽  
pp. 805-813 ◽  
Author(s):  
Ping Shi ◽  
Zhiwei Huang ◽  
Guichen Chen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Chromatin Condensation ◽  
Critical Role ◽  
S Phase ◽  
Dependent Manner ◽  
Hepatocelluar Carcinoma ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
S Phase Arrest

Rhein, an anthraquinone derivative of rhubarb, inhibits the proliferation of various human cancer cells. In this paper, we focused on studying the effects of rhein on human hepatocelluar carcinoma BEL-7402 cells and further understanding the underlying molecular mechanism in an effort to make the potential development of rhein in the treatment of cancers. Using MTT assay and flow cytometry, we demonstrate a critical role of rhein in the suppression of BEL-7402 cell proliferation in a concentration- and time-dependent manner. The increase of apoptosis rate was observed after incubation of BEL-7402 cells with rhein at 50–200 μM for 48 hours, and the cells exhibit typical apoptotic features including cellular morphological change and chromatin condensation. Moreover, rhein-induced cell cycle S-phase arrest. Additionally, after rhein treatment, expression levels of c-Myc gene were decreased, while those of caspase-3 gene were increased in a dose-dependent manner by using real-time PCR assay. The results demonstrate for the first time that cell cycle S-phase arrest is one of the mechanisms of rhein in inhibition of BEL-7402 cells. Rhein plays its role by inducing cell cycle arrest via downregulation of oncogene c-Myc and apoptosis through the caspase-dependent pathway. It is expected that rhein will be effective and useful as a new agent in hepatocelluar carcinoma treatment in the future.

scholarly journals Gene Repair in sub‐S phase Cell Populations and Cell Cycle Response to Quadruplex Oligonucleotides

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Melissa Warriner ◽  
Timothy Schwartz ◽  
Julia Engstrom ◽  
Eric Kmiec
Keyword(s):  
Cell Cycle ◽  
S Phase ◽  
Phase Cell ◽  
Cell Populations ◽  
Gene Repair

scholarly journals Anoxic Fibroblasts Activate a Replication Checkpoint That Is Bypassed By E1a

2003 ◽  
Vol 23 (24) ◽  
pp. 9032-9045 ◽  
Author(s):  
Lawrence B. Gardner ◽  
Feng Li ◽  
Xuejie Yang ◽  
Chi V. Dang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
S Phase ◽  
Low Oxygen ◽  
Replication Checkpoint ◽  
Phase Arrest ◽  
Distinct Cell ◽  
Rat Fibroblasts ◽  
Transcription Factor E2f ◽  
Cycle Regulation

ABSTRACT Little is known about cell cycle regulation in hypoxic cells, despite its significance. We utilized an experimentally tractable model to study the proliferative responses of rat fibroblasts when rendered hypoxic (0.5% oxygen) or anoxic (<0.01% oxygen). Hypoxic cells underwent G1 arrest, whereas anoxic cells also demonstrated S-phase arrest due to suppression of DNA initiation. Upon reoxygenation, only those cells arrested in G1 were able to resume proliferation. The oncoprotein E1a induced p53-independent apoptosis in anoxic cells, which when suppressed by Bcl-2 permitted proliferation despite anoxia. E1a expression led to marked increases in the transcription factor E2F, and overexpression of E2F-1 allowed proliferation in hypoxic cells, although it had minimal effect on the anoxic suppression of DNA initiation. We thus demonstrate two distinct cell cycle responses to low oxygen and suggest that alterations that lead to increased E2F can overcome hypoxic G1 arrest but that additional alterations, promoted by E1a expression, are necessary for neoplastic cells to proliferate despite anoxia.

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