Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “G2 Phase”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources
PubMedDate not supplied

The action of cisplatinum (cis-DDP) on the postnatal growth of the rat liver. Cytokinetics and ultrastructural studies.

The early and late effects of cis-DDP treatment on liver cell kinetics were analyzed after its intraperitoneal injection into 17-day old rats. Frequency of binucleate hepatocytes, cellular DNA content distribution, 3H-thymidine labelling and ultrastructure of the nuclei were analyzed. Two days after treatment, a block of mononucleate hepatocytes in the S phase and in the G2 phase was demonstrated by the increase of intermediate 2c-4c and 4c DNA values in the absence of changes in 3H-thymidine labelling; 8c binucleate cells, which are essential for the formation of tetraploid mononucleate cells, were not found. In cell nuclei, large areas of more condensed chromatin appeared, perhaps providing further evidence for a G2 block. Seven days after treatment, there was a tendency to catch up with the normal situation, as shown by the unblocking of the S phase in mononucleate cells indicated by both cytophotometry and autoradiography. The presence of 8c binucleate cells and 4c-8c mononucleate cells indicates that 4c mononucleate hepatocytes are either diploid cells in the G2 phase or true tetraploid G1 cells. The decrease in the heterochromatin areas and the appearance of hypertrophic nucleoli demonstrate an increase in the metabolic activity of the nuclei. Thirty six days after treatment, the incidence of different DNA hepatocyte classes and the 3H-thymidine labelling were already similar in control and in treated rats.

Aging↗
PubMed1995

Accumulation of wild-type p53 protein upon gamma-irradiation induces a G2 arrest-dependent immunoglobulin kappa light chain gene expression.

The exposure of cells to DNA-damaging agents leads to the accumulation of wild-type p53 protein. Furthermore, overexpression of the wild-type p53, mediated by transfection of p53-coding cDNA, induced cells to undergo apoptosis or cell differentiation. In this study we found that the gamma-irradiation that caused the accumulation of wild-type p53 in 70Z/3 pre-B cells induced, in addition to apoptosis, cell differentiation. This was manifested by the expression of the kappa light chain immunoglobulin gene that coincided with the accumulation of cells at the G2 phase. Overexpression of mutant p53 in 70Z/3 cells interferes with both differentiation and accumulation of cells at the G2 phase, as well as with apoptosis, which were induced by gamma-irradiation. Furthermore, the increment in the wild-type p53 protein level following gamma-irradiation was disrupted in the mutant p53 overproducer-derived cell lines. This suggests that mutant p53 may exert a dominant negative effect in all of these activities. Data presented here show that while p53-induced apoptosis is associated with the G1 checkpoint, p53-mediated differentiation, which may be an additional pathway to escape the fixation of genetic errors, may be associated with the G2 growth arrest phase.

Amino Acid Sequence↗
PubMed1994

Effect of staurosporine on MOLT-4 cell progression through G2 and on cytokinesis.

Staurosporine (SSP) is an inhibitor of a variety of protein kinases with an especially high affinity towards protein kinase C. Whereas SSP has been shown to halt the cell cycle progression of various normal, nontransformed cell types in G1, most virus transformed or tumor cells are unaffected in G1 but arrest in G2 phase. SSP has also been observed to increase the appearance of cells with higher DNA content, suggestive of endoreduplication, in cultures of tumor cells. Using multivariate flow cytometry (DNA content vs. expression of cyclin B, nuclear p120 protein, or protein reactive with Ki-67 antibody) which makes it possible to discriminate cells with identical DNA content but at different phases of the cycle, we have studied the cell cycle progression of human lymphocytic leukemic MOLT-4 cells in the presence of 0.1 microM SSP. MOLT-4 cells did not arrest in G1 or G2 phase in the presence of the inhibitor. Rather, they failed to undergo cytokinesis, entering G1 phase at higher DNA ploidy (tetraploidy; G1T), and then progressed through ST (rereplication) into G2T and MT. The rates of entrance to G2 and G2T were essentially identical, indicating that the rates of cell progression through S and ST as well as through G2 and G2T, respectively, were similar. Cells entrance to mitosis and mitotic chromatin condensation were also similar at the diploid and tetraploid DNA content level and were unaffected by 0.1 microM SSP. No evidence of growth imbalance (altered protein or RNA to DNA ratio) was observed in the case of tetraploid cells. The data show that, in the case of MOLT-4 cells, all events associated with the chromosome or DNA cycle were unaffected by SSP; the only target of the inhibitor appears to be kinase(s) controlling cytokinesis.

Alkaloids↗
PubMed2006

Phosphatidylcholine catabolism in the MCF-7 cell cycle.

The catabolism of phosphatidylcholine (PtdCho) appears to play a key role in regulating the net accumulation of the lipid in the cell cycle. Current protocols for measuring the degradation of PtdCho at specific cell-cycle phases require prolonged periods of incubation with radiolabelled choline. To measure the degradation of PtdCho at the S and G2 phases in the MCF-7 cell cycle, protocols were developed with radiolabelled lysophosphatidylcholine (lysoPtdCho), which reduces the labelling period and minimizes the recycling of labelled components. Although most of the incubated lysoPtdCho was hydrolyzed to glycerophosphocholine (GroPCho) in the medium, the kinetics of the incorporation of label into PtdCho suggests that the labelled GroPCho did not contribute significantly to cellular PtdCho formation. A protocol which involved exposing the cells twice to hydroxyurea, was also developed to produce highly synchronized MCF-7 cells with a profile of G1:S:G2/M of 90:5:5. An analysis of PtdCho catabolism in the synchronized cells following labelling with lysoPtdCho revealed that there was increased degradation of PtdCho in early to mid-S phase, which was attenuated in the G2/M phase. The results suggest that the net accumulation of PtdCho in MCF-7 cells may occur in the G2 phase of the cell cycle.

Cell Cycle↗
PubMed2004

Proteasome-mediated degradation of cell division cycle 25C and cyclin-dependent kinase 1 in phenethyl isothiocyanate-induced G2-M-phase cell cycle arrest in PC-3 human prostate cancer cells.

Phenethyl isothiocyanate (PEITC), a constituent of many cruciferous vegetables, offers significant protection against cancer in animals induced by a variety of carcinogens. The present study demonstrates that PEITC suppresses proliferation of PC-3 cells in a dose-dependent manner by causing G(2)-M-phase cell cycle arrest and apoptosis. Interestingly, phenyl isothiocyanate (PITC), which is a structural analogue of PEITC but lacks the -CH(2) spacers that link the aromatic ring to the -N=C=S group, neither inhibited PC-3 cell viability nor caused cell cycle arrest or apoptosis. These results indicated that even a subtle change in isothiocyanate (ITC) structure could have a significant impact on its biological activity. The PEITC-induced cell cycle arrest was associated with a >80% reduction in the protein levels of cyclin-dependent kinase 1 (Cdk1) and cell division cycle 25C (Cdc25C; 24 h after treatment with 10 micro M PEITC), which led to an accumulation of Tyr(15) phosphorylated (inactive) Cdk1. On the other hand, PITC treatment neither reduced protein levels of Cdk1 or Cdc25C nor affected Cdk1 phosphorylation. The PEITC-induced decline in Cdk1 and Cdc25C protein levels and cell cycle arrest were significantly blocked on pretreatment of PC-3 cells with proteasome inhibitor lactacystin. A 24 h exposure of PC-3 cells to 10 micro M PEITC, but not PITC, resulted in about 56% and 44% decrease in the levels of antiapoptotic proteins Bcl-2 and Bcl-X(L), respectively. However, ectopic expression of Bcl-2 failed to alter sensitivity of PC-3 cells to growth inhibition or apoptosis induction by PEITC. Treatment of cells with PEITC, but not PITC, also resulted in cleavage of procaspase-3, procaspase-9, and procaspase-8. Moreover, the PEITC-induced apoptosis was significantly attenuated in the presence of general caspase inhibitor and specific inhibitors of caspase-8 and caspase-9. In conclusion, our data indicate that PEITC-induced cell cycle arrest in PC-3 cells is likely due to proteasome-mediated degradation of Cdc25C and Cdk1, and ectopic expression of Bcl-2 fails to confer resistance to PEITC-induced apoptosis. Furthermore, the results of the present study point toward involvement of both caspase-8- and caspase-9-mediated pathways in apoptosis induction by PEITC.

Acetylcysteine↗
PubMed1995

[Relationship between CENP-B gene expression and the cell cycle].

The centromere/kinetochore is a specialized structure at the primary constriction of mammalian chromosomes. It participates in and is necessary for the mitotic chromosome movement. Centromere Protein B(CENP-B) is a highly conserved protein located at the centromere/kinetochore region. In this article, we explore the relationship between CENP-B expression and cell proliferation. HeLa cells were synchronized at different phases of the cell cycle and the synchronized cells were examined by flow cytometry and 3H-TdR labelling. ACA immunostaining showed the discrete single spots in nuclei of the cells at G1 and S phase, and spots in pairs mostly in those at G2 phase. Dot blot and Northern blot indicated that CENP-B gene was expressed at all phases of the cell cycle, but the expression level very much different with the highest at G2 phase and the lowest at S phase. Interestingly relatively high expression of CENP-B gene was also found in M phase, showing the continuity of the CENP-B gene expression during the cell cycle. This continuity implies a possibility that the assembly of the new centromere/kinetochore can not occur until centromere proteins reach a critical concentration when cells enter S phase and G 2 phase. Also, the continuous expression of centromere proteins may be necessary for the centromere/kinetochore function. In addition, the relationship between CENP-B gene expression and the nuclear skeleton was investigated. The nuclear skeleton-associated DNA extracted after Bam HI digestion were hybridized with 32P-labelled cDNA of CENP-B gene by means of Southern blot technique. The results that there stronger positive hybridization reaction in G 2 phase than in S phase indicated that CENP-B gene was more closely associated with the nuclear skeleton in G 2 phase cells than in S phase cells, which was in consistence with the level of the CENP-B gene expression at G 2 and S phase cells.

Autoantigens↗
PubMed1998

Cdc2-independent induction of premature mitosis by okadaic acid in HeLa cells.

The induction of premature mitosis by okadaic acid (OA) in HeLa cells in S-phase or in G2-phase has been studied using light microscopy, immunofluorescence, and immunochemical techniques. The observations indicate an involvement of a cdc2-independent pathway in these cells. It has been claimed that inhibition of an OA-sensitive phosphatase, possibly of PP1, induces activation of a kinase which is sensitive to staurosporine and Zn2+. This kinase brings about mitosis-specific cytoskeletal rearrangements, chromosome condensation, and nuclear envelope breakdown, inducing a mitosis-like state. However, other mitotic events do not follow. The possibility that this kinase may be a NIMA-like Nek2 kinase is discussed.

CDC2 Protein Kinase↗
PubMed1975

Epidermal chalone and cyclic AMP: an in vivo study.

Water extracts of skin contain two factors that inhibit epidermal cell proliferation: one substance inhibits epidermal cells in the G2 phase (the epidermal G2 inhibitor), and another inhibits the transit of cells from the G1 phase into the S phase (the epidermal G1 inhibitor). Pretreatment of mice with a beta-receptor antagonist (propranolol) abolished the activity of the G2 inhibitor but not that of the G1 inhibitor. After pretreatment with both propranolol and a phosphodiesterase inhibitor (caffine)the G2 inhibitor had full effect. Cafine alone had a moderately inhibitory effect on epidermal G2 cells and enhanced the depressing effect of the G1 inhibitor on epidermal DNA synthesis. AMP level in epidermis to be active. Cyclic AMP is probably also involved in the regulation of the rate of transit of epidermal G1 cells into the S phase but the epidermal cyclic AMP level seems not to be so critical for the efficacy of the epidermal G2 inhibitor in epidermal cell differentiation.

Animals↗
PubMed2000

NF-Y mediates the transcriptional inhibition of the cyclin B1, cyclin B2, and cdc25C promoters upon induced G2 arrest.

During normal cell cycles, the function of mitotic cyclin-cdk1 complexes, as well as of cdc25C phosphatase, is required for G2 phase progression. Accordingly, the G2 arrest induced by DNA damage is associated with a down-regulation of mitotic cyclins, cdk1, and cdc25C phosphatase expression. We found that the promoter activity of these genes is repressed in the G2 arrest induced by DNA damage. We asked whether the CCAAT-binding NF-Y modulates mitotic cyclins, cdk1, and cdc25C gene transcription during this type of G2 arrest. In our experimental conditions, the integrity of the CCAAT boxes of cyclin B1, cyclin B2, and cdc25C promoters, as well as the presence of a functional NF-Y complex, is strictly required for the transcriptional inhibition of these promoters. Furthermore, a dominant-negative p53 protein, impairing doxorubicin-induced G2 arrest, prevents transcriptional down-regulation of the mitotic cyclins, cdk1, and cdc25C genes. We conclude that, as already demonstrated for cdk1, NF-Y mediates the transcriptional inhibition of the mitotic cyclins and the cdc25C genes during p53-dependent G2 arrest induced by DNA damage. These data suggest a transcriptional regulatory role of NF-Y in the G2 checkpoint after DNA damage.

CCAAT-Binding Factor↗
PubMed1976

Deficit in DNA content relative to histones in X-irradiated HeLa cells.

The DNA and histone content of HeLa S-3 cell cultures was measured by direct mass assays 21 hours after 1000 rad of X-irradiation, when the cells were arrested in G2 phase. The nuclear DNA content of such cultures was found to be deficient (73% of control values). In contrast, the synthesis of nuclear histones persisted, and the total histone content was close to 100% of control values. When synchronously-growing cultures were irradiated in mid-S phase and examined 3-5 hours later in G2 phase, both DNA and histone content were equal to control values.

DNA↗
PubMed1983

Microspectrophotometric and autoradiographic study of the timing and duration of pre-meiotic DNA synthesis in Paramecium caudatum.

Timing and duration of pre-meiotic G1, S and G2 phases in Paramecium caudatum have been clarified by microspectrophotometry of DNA content and autoradiography with [3H]thymidine ([3H]dThd) and [3H]deoxyuridinemonophosphate ([3H]dUMP). Microspectrophotometric measurement of DNA content showed that cells in stationary phase have a G1 micronucleus, and that pre-meiotic DNA synthesis begins with the micronuclear swelling and ends immediately before the nucleus enters meiotic prophase. The results indicate that the micronucleus is in G1 during the first 1.5 h after onset of mating reaction at 25 degrees C and in pre-meiotic S phase during the following 1 h, and that G2 phase is very short or lacking. Therefore, in P. caudatum, the transition point from pre-meiotic interphase to meiotic prophase is at or very close to the end of pre-meiotic DNA synthesis. Autoradiographic study showed that although [3H]dThd and [3H]dUMP were well utilized in pre-mitotic DNA synthesis, only [3H]dUMP was well utilized in pre-meiotic DNA synthesis. [3H]dThd was utilized very little in pre-meiotic DNA synthesis even if the precursor was taken into the cell, suggesting that the activity of thymidine kinase is low in these cells.

Animals↗
PubMed1992

Induction by bufalin of differentiation of human leukemia cells HL60, U937, and ML1 toward macrophage/monocyte-like cells and its potent synergistic effect on the differentiation of human leukemia cells in combination with other inducers.

We have recently demonstrated that bufalin is a new potent inducer of the differentiation of human myeloid leukemia cells. The present work was carried out to examine further the effect of bufalin on the growth and characteristics of human leukemia-derived cell lines U937, ML1, and HL60. At concentrations of 5-10 nM, bufalin decreased the growth of ML1 cells preferentially at the G2 phase and U937 cells at the S and G2 phases of the cell cycle. Bufalin, under these conditions, induced the differentiation of U937, ML1, and HL60 cells to monocyte/macrophage-like cells by measuring the expression of various differentiation markers, as assessed by morphology and histochemistry, and ability to phagocytose latex particles, to reduce nitroblue tetrazolium, and to develop Fc receptors. U937 and ML1 cells started to differentiate at 4 and 6 h, respectively, after treatment with 10 nM bufalin and showed maximum differentiation 72 h later. At present, a mechanism for the bufalin-mediated induction of the differentiation of these human leukemia cells remains to be determined. The combination of bufalin with all-trans retinoic acid, 1 alpha,25-dihydroxyvitamin D3, 4'-demethylepipodophyllotoxin ethylidene-beta-D-glucoside (VP16), or human gamma-interferon synergistically induced the differentiation of HL60 and U937 cells. A similar effect on ML1 cells was observed with the combination of bufalin with VP16 or human rTNF-alpha. These results suggest that bufalin in combination with VP16, all-trans retinoic acid, 1 alpha,25-dihydroxyvitamin D3, rTNF-alpha, or gamma-interferon may be very useful in the differentiation of human leukemia.

Antineoplastic Agents↗
PubMed1998

Explaining differences in sensitivity to killing by ionizing radiation between human lymphoid cell lines.

We surveyed five human hematopoietic cell lines (HSB-2, MOLT-4, Reh, CEM, and HL-60) to determine whether any simple correlates with sensitivity to killing by gamma-irradiation might be revealed. The clonogenic survival gamma-ray dose-response curves for these cell lines cover a wide range of sensitivities. Consistent with previous results for murine hematopoietic cell lines, there was a clear correlation between the rapidity with which irradiation induced apoptosis and clonogenic radiosensitivity of a cell line, although the relationship between timing of apoptosis and radiosensitivity differed between human and murine cell lines. Flow cytometric determination of cell cycle distribution after irradiation showed that differences between human hematopoietic cell lines, in the rate of induction of apoptosis, were generally related to the functioning of cell cycle checkpoints. Whereas the rapidly dying and radiosensitive HSB-2 cell line underwent apoptosis from different points in the cell cycle, the more slowly dying cell lines showed a variety of cell cycle arrest profiles and initiated apoptosis after accumulation of cells in the G2 phase. The lag-phase between arrest in G2 and induction of apoptosis was comparable for MOLT-4, Reh, and CEM; however, HL-60 cells showed a markedly longer G2 arrest that correlated with their greater radioresistance. The results suggest that the total length of time available for DNA damage repair (irrespective of whether this time accrues as blockage in G1, S, or G2), prior to potential activation of apoptosis, is a critical determinant of radiosensitivity in human hematopoietic cell lines. Comparison of the p53 status of these cell lines suggested that mutations in the TP53 gene are contributing to the delay of induction of apoptosis seen in the more radioresistant cell lines. The sensitivity of MOLT-4 and HL-60 cells to killing by DNA-associated 125I decays was determined and was found to correlate with the relative sensitivity of these lines to gamma-irradiation. The highly localized deposition of energy by 125I decays argues that DNA damage is a potent initiator of apoptosis in these cell lines. The results presented suggest that differences in the radiosensitivity of the cell lines examined reflect differences in the rapidity of induction of apoptosis and that radiation-induced cell death in hematopoietic cells can be explained as a response to DNA damage.

Apoptosis↗
PubMed1982

Patterns of histone variant synthesis can distinguish G0 from G1 cells.

Quiescent Chinese hamster ovary cells, as well as three other types of quiescent cells, synthesize histone at a reduced but significant rate. The variant patterns of the histone synthesis in quiescent, S-phase and G1-phase and G2-phase cells ali differed from each other. H3.3 was the only H3 variant synthesized in quiescent and in G1 and G2 cells. All four H2A variants were synthesized in quiescent and S-phase cells, but only H2A.X and H2A.Z were synthesized in G1 and G2 cells. No part of G1 or the G1-S transition could be found with an H2A synthesis pattern like that in quiescent cells. These findings suggest that the quiescent state is not part of G1, but that it is a separate and discrete state.

Animals↗
PubMed1989

Flow cytometric detection of mitotic cells using the bromodeoxyuridine/DNA technique in combination with 90 degrees and forward scatter measurements.

Mitotic cells could be well discriminated from the cells in the G1-, S- and G2-phases of the cell cycle using pulse labeling of S-phase cells with bromodeoxy-uridine (BrdUrd) and staining of the cells for incorporated BrdUrd and total DNA content. Unlabeled G2- and M-phase cells could be measured as two separate peaks according to propidium iodide fluorescence. M-phase cells showed lower propidium iodide fluorescence emission compared to G2-phase cells. The fluorescence difference of M- and G2-phase cells was caused by the different thermal denaturation of their DNA. Best separation of M- and G2-phase cells was obtained after 30-50 min heat treatment at 95 degrees C. Mitotic index could be measured if no unlabeled S-phase cells were present in the cell culture. With additional measurements of 90 degree scatter and/or forward scatter signals, mitotic cells could be clearly discriminated from both unlabeled G2- and S-phase cells. The correct discrimination (about 99%) of mitotic cells from interphase cells was verified by visual analysis of the nuclear morphology after selective sorting. Unlabeled and labeled mitotic cells could be observed as pulse-labeled cells progressed through the cell cycle. We conclude that this modified BrdUrd/DNA technique using prolonged thermal denaturation and the simultaneous measurement of scatter signals may offer additional information especially in the presence of BrdUrd-unlabeled S-phase cells.

Animals↗
PubMed1993

X-ray-induced chromatid damage in cells from Down syndrome and Alzheimer disease patients in relation to DNA repair and cancer proneness.

Frequencies of chromatid aberrations in response to G2-phase x-irradiation were compared in PHA-stimulated blood lymphocytes from healthy control subjects, Down syndrome (DS) patients, and Alzheimer disease (AD) patients. In cells arrested with Colcemid immediately (0-30 min) after x-irradiation, DS, AD, and control cells showed similar high frequencies of chromatid breaks and gaps, representing unrepaired DNA strand breaks. Frequencies had decreased in AD and control cells arrested 30-90 min after irradiation. However, DS cells had two- to three-fold higher frequencies than AD or control cells. This result indicates deficient repair of the DNA damage in DS cells. Similar responses were obtained with lymphocytes from four of seven DS parents tested and with skin fibroblasts from DS patients compared to age-matched controls. Addition of 1-beta-D-arabinofuranosylcytosine (ara-C), an inhibitor of the repair polymerase, after x-irradiation during G2 phase increased the frequencies of chromatid breaks and gaps in lymphocytes from control and AD donors significantly more than in those from DS patients. This result indicates a deficiency in DS cells in incision at sites of x-ray-induced damage. Thus DS, like other cancer-prone genetic disorders, has a G2-phase DNA repair deficiency in strand break repair and also a second DNA repair deficiency in incision activity.

Adult↗
PubMed1996

Two Arabidopsis cyclin promoters mediate distinctive transcriptional oscillation in synchronized tobacco BY-2 cells.

Cyclins are cell cycle regulators whose proteins oscillate dramatically during the cell cycle. Cyclin steady-state mRNA levels also fluctuate, and there are indications that both their rate of transcription and mRNA stability are under cell cycle control. Here, we demonstrate the transcriptional regulation of higher eukaryote cyclins throughout the whole cell cycle with a high temporal resolution. The promoters of two Arabidopsis cyclins, cyc3aAt and cyc1At, mediated transcriptional oscillation of the beta-glucuronidase (gus) reporter gene in stably transformed tobacco BY-2 cell lines. The rate of transcription driven by the cyc3aAt promoter was very low during G1, slowly increased during the S phase, peaked at the G2 phase and G2-to-M transition, and was down-regulated before early metaphase. In contrast, the rate of the cyc1At-related transcription increased upon exit of the S phase, peaked at the G2-to-M transition and during mitosis, and decreased upon exit from the M phase. This study indicates that transcription mechanisms that seem to be conserved among species play a significant role in regulating the mRNA abundance of the plant cyclins. Furthermore, the transcription patterns of cyc3aAt and cyc1At were coherent with their slightly higher sequence similarity to the A and B groups of animal cyclins, respectively, suggesting that they may fulfill comparable roles during the cell cycle.

Animals↗
PubMed2004

Cell cycle checkpoints and their impact on anticancer therapeutic strategies.

Cells contain numerous pathways designed to protect them from the genomic instability or toxicity that can result when their DNA is damaged. The p53 tumor suppressor is particularly important for regulating passage through G1 phase of the cell cycle, while other checkpoint regulators are important for arrest in S and G2 phase. Tumor cells often exhibit defects in these checkpoint proteins, which can lead to hypersensitivity; proteins in this class include ataxia-telangiectasia mutatated (ATM), Meiotic recanbination 11 (Mre11), Nijmegen breakage syndrome 1 (Nbs 1), breast cancer susceptibility genes 1 and 2 (BRCA1), and (BRCA2). Consequently, tumors should be assessed for these specific defects, and specific therapy prescribed that has high probability of inducing response. Tumors defective in p53 are frequently considered resistant to apoptosis, yet this defect also provides an opportunity for targeted therapy. When their DNA is damaged, p53-defective tumor cells preferentially arrest in S or G2 phase where they are susceptible to checkpoint inhibitors such as caffeine and UCN-01. These inhibitors preferentially abrogate cell cycle arrest in p53-defective cells, driving them through a lethal mitosis. Wild type p53 can prevent abrogation of arrest by elevating levels of p21(waf1) and decreasing levels of cyclins A and B. During tumorigenesis, tumor cells frequently loose checkpoint controls and this facilitates the development of the tumor. However, these defects also represent an Achilles heel that can be targeted to improve current therapeutic strategies.

Animals↗