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Results for “Cell Cycle Checkpoints”

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At least 181 records · Page 10Linked to original sources
PubMed1996

p53 induction, cell cycle checkpoints, and apoptosis in DNAPK-deficient scid mice.

The p53 tumor suppressor protein is rapidly induced following treatment of cells with agents which cause DNA double strand breaks (dsbs) leading to cell cycle arrest and/or apoptosis. Scid mutant mice are defective in repair of DNA dsbs which was recently shown to be due to lack of DNA-dependent protein kinase (DNAPK) activity. DNAPK is normally activated by DNA dsbs and phosphorylates the p53 protein. Here we tested the hypothesis that DNAPK transduces the signal from DNA dsbs to p53 induction. P53 protein was properly induced in intestinal crypt cells of irradiated scid mice and was functional as detected by the large increase in apoptotic cells. P53 induction was prolonged, consistent with DNA dsbs as the signal to induce p53. Spontaneous levels of apoptosis were elevated suggesting that scid mice are sensitive indicators of spontaneously generated DNA dsbs. Primary scid fibroblasts underwent normal G1 and G2 arrest in response to doxorubicin. DNAPK is not required for p53 induction, cell cycle arrest, or apoptosis after DNA damage.

Animals↗
PubMed1997

Cell cycle checkpoints and DNA repair in Nijmegen breakage syndrome.

Nijmegen breakage syndrome is characterized by a variable T cell and B cell immunodeficiency, growth failure, and an increased risk of malignancy. It is inherited in an autosomal recessive manner and is biochemically related to ataxia-telangiectasia. Cells from a patient with Nijmegen breakage syndrome were unable to arrest cell cycle progression after exposure to ionizing radiation, and BrdU incorporation into newly synthesized DNA was uninhibited, demonstrating that these cells have an aberrant response to radiation exposure. Although gross chromosomal breakage was observed, dinucleotide repeat segments were stable over time, suggesting that other types of DNA stability were not affected. DNA-PK activity, which is mediated by a protein related to the ataxia-telangiectasia gene product and is intimately involved in DNA repair and VDJ recombination, was normal in cells from an NBS patient. Therefore, cells from patients with Nijmegen breakage syndrome have an abnormal response to radiation exposure similar to that seen in ataxia-telangiectasia.

Abnormalities, Multiple↗
PubMed1997

Ultraviolet light-induced G2 phase cell cycle checkpoint blocks cdc25-dependent progression into mitosis.

In response to low doses of ultraviolet (U.V.) radiation, cells undergo a G2 delay. In this study we have shown that the G2 delay results in the accumulation of inactive forms of cyclin B1/cdc2 and both the G2 and mitotic complexes of cyclin A/cdk. This appears to be through a block in the cdc25-dependent activation of these complexes. The expression and localisation of cyclin A and cyclin B1/cdk complexes are similar in U.V.-induced G2 delay and normal early G2 phase cells. Cdc25B and cdc25C also accumulate to normal G2 levels in U.V. irradiated cells, but the mitotic phosphorylation associated with increased activity of both cdc25B and cdc25C is absent. The cdc25B accumulates in the nucleus of U.V. irradiated cells and in normal G2 phase cells. Thus the block in cyclin B/cdc2 activation is in part due to the physical separation of cyclin B/cdc2, localised in the cytoplasm, from the cdc25B and cdc25C phosphatases localised in the nucleus. The data positions the U.V.-induced G2 checkpoint at either the S/G2 transition or early G2 phase, prior to the activation of cyclin A/cdk2.

CDC2 Protein Kinase↗
PubMed1995

p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts.

Increased expression of wild-type p53 in response to DNA damage arrests cells late in the G1 stage of the cell cycle by stimulating the synthesis of inhibitors of cyclin-dependent kinases, such as p21/WAF1. To study the effects of p53 without the complication of DNA damage, we used tetracycline to regulate its expression in MDAH041 human fibroblasts that lack endogenous p53. When p53 is expressed at a level comparable to that induced by DNA damage in other cells, most MDAH041 cells arrested in G1, but a significant fraction also arrested in G2/M. Cells released from a mimosine block early in S phase stopped predominantly in G2/M in the presence of p53, confirming that p53 can mediate arrest at this stage, as well as in G1. In these cells, there was appreciable induction of p21/WAF1. MDAH041 cells arrested by tetracycline-regulated p53 for as long as 20 days resumed growth when the p53 level was lowered, in striking contrast to the irreversible arrest mediated by DNA damage. Therefore, irreversible arrest must involve processes other than or in addition to the interaction of p53-induced p21/WAF1 with G1 and G2 cyclin-dependent kinases.

Cell Cycle↗
PubMed2001

DNA damage-induced cell cycle checkpoints involve both p53-dependent and -independent pathways: role of telomere repeat binding factor 2.

Treatment of colon cancer cells with MNNG causes DNA damage with reduced telomeric signals in a p53-dependent manner, but increased cell cycle arrest in S-G(2)/M by both p53-dependent and independent mechanisms. Results also indicate that cellular levels of TRF2 may play a critical role in MNNG-induced cell cycle arrest and apoptosis of colon cancer cells.

Apoptosis↗
PubMed1997

Effect of 1 Gy X-rays in G1 phase on activation of cell cycle checkpoints in human lymphocytes: role played by chromosomal aberrations.

The effect of X-irradiation (1 Gy) during G1 on the transition from G1 to S and on the length of G2 over cell cycles subsequent to irradiation was studied in human lymphocytes from six different donors. After irradiation a delay was observed in the onset of S phase, as was an extension of the G2 phase lasting throughout the three to four subsequent cell divisions. The extension of G2 and of the cell cycle as a whole is partly related to the presence of chromosome aberrations in the cell. This is demonstrated by: (i) the presence of a larger number of chromosome aberrations in M1 cells corresponding to sampling times longer after that of irradiation; (ii) the presence of a larger number of chromosome aberrations in cells with a longer G2. The most significant chromosome aberrations in this respect are isochromatid fragments. Lastly, we observed that irradiation during G1 activates another checkpoint governing the way mitosis proceeds. This takes the form of an extension of metaphase; in this case also, in some cells, activation of a possible checkpoint during preanaphase seems to be related to the presence of aberrations.

Adult↗
PubMed1999

Phytochrome-induced expression of lig1, a homologue of the fission yeast cell-cycle checkpoint gene hus1, is associated with the developmental switch in Physarum polycephalum plasmodia.

Lig1 was found in a differential-display screen for early genes expressed during phytochrome-controlled sporulation of Physarum polycephalum plasmodia. A stretch of 218 amino acids of the predicted sequence of Lig1 shares 32% sequence identity to that of the Schizosaccharomyces pombe cell-cycle and DNA-damage checkpoint gene hus1. In addition Lig1 is homologous to proteins of unknown function in Homo sapiens (35% identity) and Mus musculus (31% identity). Induction of lig1 expression was found to be controlled downstream from the point of integration of the phytochrome-activated pathway and the pathway sensing the metabolic state, but upstream of the developmental switch. The lig1 expression level in individual plasmodia correlated positively with the probability to sporulate. Sensory control of the lig1 expression level and its association with the developmental switch suggests a possible mechanism for the coordination of differentiation and the control of cell-cycle progression during the sporulation of P. polycephalum.

Amino Acid Sequence↗
PubMed1998

Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints.

ATR, a phosphatidylinositol kinase-related protein homologous to ataxia telangiectasia mutated (ATM), is important for the survival of human cells following many forms of DNA damage. Expression of a kinase-inactive allele of ATR (ATRkd) in human fibroblasts causes increased sensitivity to ionizing radiation (IR), cis-platinum and methyl methanesulfonate, but only slight UV radiation sensitivity. ATRkd overexpression abrogates the G2/M arrest after exposure to IR, and overexpression of wild-type ATR complements the radioresistant DNA synthesis phenotype of cells lacking ATM, suggesting a potential functional overlap between these proteins. ATRkd overexpression also causes increased sensitivity to hydroxyurea that is associated with microtubule-mediated nuclear abnormalities. These observations are consistent with uncoupling of certain mitotic events from the completion of S-phase. Thus, ATR is an important component of multiple DNA damage response pathways and may be involved in the DNA replication (S/M) checkpoint.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1997

HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint.

Hox11 is an orphan homeobox gene that controls the genesis of the spleen. HOX11 is also oncogenic, having been isolated from a chromosomal breakpoint in human T-cell leukaemia. Transgenic mice that redirected HOX11 to the thymus demonstrated cell-cycle aberration and progression to malignancy. We observed that the protein HOX11 interacted with protein serine-threonine phosphatase 2A catalytic subunit (PP2AC), as well as protein phosphatase 1 (PP1C) in mammalian cells. Inhibition of PP2A can regulate the cell cycle and control the activation of maturation-promoting factor in Xenopus oocytes. Microinjection of HOX11 into Xenopus oocytes arrested at the G2 phase of the cell cycle promoted progression to the M phase. G2 arrest can be induced by gamma-irradiation, but is eliminated by expression of HOX11 within a T-cell line. Thus HOX11 is a cellular oncogene that targets PP2A and PP1, both of which are targets for oncogenic viruses and chemical tumour promoters. This interaction suggests a mechanism by which a homeobox can alter the cell cycle.

Animals↗
PubMed2002

GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress.

Gadd45a (Gadd45), Gadd45b (MyD118), and Gadd45g (CR6) constitute a family of evolutionarily conserved, small, acidic, nuclear proteins, which have been implicated in terminal differentiation, growth suppression, and apoptosis. How Gadd45 proteins function in negative growth control is not fully understood. Recent evidence has implicated Gadd45a in inhibition of cdc2/cyclinB1 kinase and in G2/M cell cycle arrest. Yet, whether Gadd45b and/or Gadd45g function as inhibitors of cdc2/cyclinB1 kinase and/or play a role in G2/M cell cycle arrest has not been fully established. In this work, we show that Gadd45b and Gadd45g specifically interact with the Cdk1/CyclinB1 complex, but not with other Cdk/Cyclin complexes, in vitro and in vivo. Data also has been obtained that Gadd45b and Gadd45g, as well as GADD45a, interact with both Cdk1 and cyclinB1, resulting in inhibition of the kinase activity of the Cdk1/cyclinB1 complex. Inhibition of Cdk1/cyclinB1 kinase activity by Gadd45b and Gadd45a was found to involve disruption of the complex, whereas Gadd45g did not disrupt the complex. Moreover, using RKO lung carcinoma cell lines, which express antisense Gadd45 RNA, data has been obtained, which indicates that all three Gadd45 proteins are likely to cooperate in activation of S and G2/M checkpoints following exposure of cells to UV irradiation.

3T3 Cells↗
PubMed1996

Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways.

Mutants of the Saccharomyces cerevisiae ataxia telangiectasia mutated (ATM) homolog MEC1/SAD3/ESR1 were identified that could live only if the RAD53/SAD1 checkpoint kinase was overproduced. MEC1 and a structurally related gene, TEL1, have overlapping functions in response to DNA damage and replication blocks that in mutants can be provided by overproduction of RAD53. Both MEC1 and TEL1 were found to control phosphorylation of Rad53p in response to DNA damage. These results indicate that RAD53 is a signal transducer in the DNA damage and replication checkpoint pathways and functions downstream of two members of the ATM lipid kinase family. Because several members of this pathway are conserved among eukaryotes, it is likely that a RAD53-related kinase will function downstream of the human ATM gene product and play an important role in the mammalian response to DNA damage.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1998

Fission yeast rad12+ regulates cell cycle checkpoint control and is homologous to the Bloom's syndrome disease gene.

The human BLM gene is a member of the Escherichia coli recQ helicase family, which includes the Saccharomyces cerevisiae SGS1 and human WRN genes. Defects in BLM are responsible for the human disease Bloom's syndrome, which is characterized in part by genomic instability and a high incidence of cancer. Here we describe the cloning of rad12+, which is the fission yeast homolog of BLM and is identical to the recently reported rhq1+ gene. We showed that rad12 null cells are sensitive to DNA damage induced by UV light and gamma radiation, as well as to the DNA synthesis inhibitor hydroxyurea. Overexpression of the wild-type rad12+ gene also leads to sensitivity to these agents and to defects associated with the loss of the S-phase and G2-phase checkpoint control. We showed genetically and biochemically that rad12+ acts upstream from rad9+, one of the fission yeast G2 checkpoint control genes, in regulating exit from the S-phase checkpoint. The physical chromosome segregation defects seen in rad12 null cells combined with the checkpoint regulation defect seen in the rad12+ overproducer implicate rad12+ as a key coupler of chromosomal integrity with cell cycle progression.

Adenosine Triphosphatases↗