Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Soft tissue sarcoma (STS) is a malignant neoplasm, arising in mesenchymal tissues, that is difficult to treat clinically because it can be highly resistant to chemo-radiotherapy. At present, the mechanism of that resistance remains unclear. Cell cycle checkpoints engender strict control of cell proliferation, arresting the cell cycle to provide time for repair or apoptosis when DNA damage is induced by unprogrammed extrinsic events. These pathways involve at least two checkpoints: one at the G1/S transition and one at the G2/M transition. The p53 gene, which is mutated in several malignant tumors, plays an important role in DNA repair at the G1/S transition; however, there is little information on the G2/M checkpoint in STS. In the present study, several proteins (phospho-p53, -cdc25, -cdc2, -Chk1 and -Chk2) involved in checkpoint pathways were investigated using immunohistochemistry in STS specimens. Most STSs maintain a well-preserved G2/M checkpoint despite the loss of the G1/S checkpoint (phospho-p53: 4.9% (2/41); -cdc25: 41% (17/41); -cdc2: 61% (25/41); -Chk1: 29% (12/41); -Chk2: 46% (19/41)). Furthermore, in a postoperative chemotherapy case the number of cells positive for phospho-cdc25 and -Chk2 was higher in a recurrent tumor than in the primary tumor (n = 7, P = 0.046 < 0.05, Wilcoxon signed-ranks test). These findings indicate that the G2/M checkpoint pathway is well preserved and might contribute to the chemotherapeutic resistance associated with STS.
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PMID:Human DNA damage checkpoints and their relevance to soft tissue sarcoma. 1467 91

Cell-cell and cell-extracellular matrix contacts influence cellular sensitivity to ionizing radiation. To further define the influence of these interactions on tumor cell survival and cell cycle progression after irradiation without or in combination with the phorbol ester phorbol-12-myristate-13-acetate (PMA), the radiation response of p53 wild-type A549 lung cancer cells grown on polystyrene, fibronectin (FN) or BSA was examined. Confluently growing and log-phase A549 cell cultures irradiated on FN showed significantly greater survival compared to cells irradiated on polystyrene or BSA. There was a significantly greater elevation of G(2)/M cells in FN cultures after irradiation compared to other culture conditions. PMA reduced radiation survival on all three substrata and under both log-phase and confluent culture conditions, but had no effect on the elevation of G(2)/M cells in FN cultures. Induction of Chk1 phosphorylation by irradiation was only seen in FN cultures. Chk2 and Cdk1 phosphorylation and Cdc25C expression also differed between FN and polystyrene cultures. Induction of p53 and p21 by irradiation was modulated but not inhibited by PMA, as were changes in cyclin D1 and pRb. Changes in protein expression and phosphorylation of these cell cycle regulatory proteins coincided tightly with accumulation of cells in G(2)/M after irradiation. These findings clearly demonstrate the influence of both intercellular and cell-substratum interactions on the radiation response without or in combination with PMA and differentiate between the cell survival and cell cycle effects of FN attachment.
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PMID:Fibronectin alters cell survival and intracellular signaling of confluent A549 cultures after irradiation. 1472 1

We have used genetic and microarray analysis to determine how ionizing radiation (IR) induces p53-dependent transcription and apoptosis in Drosophila melanogaster. IR induces MNK/Chk2-dependent phosphorylation of p53 without changing p53 protein levels, indicating that p53 activity can be regulated without an Mdm2-like activity. In a genome-wide analysis of IR-induced transcription in wild-type and mutant embryos, all IR-induced increases in transcript levels required both p53 and the Drosophila Chk2 homolog MNK. Proapoptotic targets of p53 include hid, reaper, sickle, and the tumor necrosis factor family member EIGER: Overexpression of Eiger is sufficient to induce apoptosis, but mutations in Eiger do not block IR-induced apoptosis. Animals heterozygous for deletions that span the reaper, sickle, and hid genes exhibited reduced IR-dependent apoptosis, indicating that this gene complex is haploinsufficient for induction of apoptosis. Among the genes in this region, hid plays a central, dosage-sensitive role in IR-induced apoptosis. p53 and MNK/Chk2 also regulate DNA repair genes, including two components of the nonhomologous end-joining repair pathway, Ku70 and Ku80. Our results indicate that MNK/Chk2-dependent modification of Drosophila p53 activates a global transcriptional response to DNA damage that induces error-prone DNA repair as well as intrinsic and extrinsic apoptosis pathways.
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PMID:Drosophila melanogaster MNK/Chk2 and p53 regulate multiple DNA repair and apoptotic pathways following DNA damage. 1472 67

Genistein, a soy isoflavone, has a wide range of biological actions that suggest it may be of use in cancer prevention. We have recently reported that it arrests hepatoma cells at G2/M phase and inhibits Cdc2 kinase activity. In the present study, we examined the signaling pathway by which genistein modulates Cdc2 kinase activity in HepG2 cells and leads to G2/M arrest, and found that it caused an increase in both Cdc2 phosphorylation and expression of the Cdc2-active kinase, Wee1. Genistein also enhanced the expression of the cell cycle inhibitor, p21waf1/cip1, which interacts with Cdc2. Furthermore, phosphorylation/inactivation of Cdc25C phosphatase, which dephosphorylates/activates Cdc2, was increased. Genistein enhanced the activity of the checkpoint kinase, Chk2, which phosphorylates/inactivates Cdc25C, induced accumulation of p53, and activated the ataxia-telangiectasia-mutated (ATM) gene. Caffeine, an ATM kinase inhibitor, inhibited these effects of genistein on Chk2, p53, and p21waf1/cip1. These findings suggest that the effect of genistein on G2/M arrest in HepG2 cells is partly due to ATM-dependent Chk2 activation, an increase in Cdc2 phosphorylation/inactivation as a result of induction of Wee1 expression, and a decrease in Cdc2 activity as a result of induction of p21waf1/cip1 expression.
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PMID:Genistein arrests hepatoma cells at G2/M phase: involvement of ATM activation and upregulation of p21waf1/cip1 and Wee1. 1475 71

It has been estimated that approximately 1% of the general population are ataxia telangiectasia (AT) mutated (ATM) heterozygotes. The ATM protein plays a central role in DNA-damage response pathways; however, the functional consequences of the presence of either heterozygous truncating or missense mutations on ATM expression and the ionising radiation (IR)-induced cellular phenotype remain to be fully determined. To investigate this relationship, the ATM mRNA and protein levels and several cellular end points were characterised in 14 AT heterozygote (AT het) lymphoblastoid cell lines, compared to normal and AT homozygote lines. The AT het cell lines displayed a wide range of IR-induced responses: despite lower average levels of ATM mRNA and protein expression compared to normal cells, 13 out of 14 were capable of phosphorylating the ATM substrates p53-ser15 and Chk2, leading to a normal cell cycle progression after irradiation. However, cell survival was lower than in the normal cell lines. The presence of a missense compared to a truncating mutation was associated with lower cell survival after exposure to 2 Gy irradiation (P=0.005), and a higher level of ATM mRNA expression (P=0.047). Our results underline the difficulty in establishing a reliable test for determining ATM heterozygosity.
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PMID:Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers. 1497 Aug 66

The retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control to apoptosis and is critical for normal development and cancer prevention. Here we define a transcription-mediated pathway in which deregulation of E2F1 by ectopic E2F expression or Rb inactivation by E7 of human papillomavirus type 16 signals apoptosis by inducing the expression of Chk2, a component of the DNA damage response. E2F1- and E7-mediated apoptosis are compromised in cells from patients with the related disorders ataxia telangiectasia and Nijmegen breakage syndrome lacking functional Atm and Nbs1 gene products, respectively. Both Atm and Nbs1 contribute to Chk2 activation and p53 phosphorylation following deregulation of normal Rb growth control. E2F2, a related E2F family member that does not induce apoptosis, also activates Atm, resulting in phosphorylation of p53. However, we found that the key commitment step in apoptosis induction is the ability of E2F1, and not E2F2, to upregulate Chk2 expression. Our results suggest that E2F1 plays a central role in signaling disturbances in the Rb growth control pathway and, by upregulation of Chk2, may sensitize cells to undergo apoptosis.
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PMID:Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. 1502 84

The kinase Chk2 and tumor suppressor p53 participate in an ill defined regulatory interaction in mammalian cells. The abundance of Chk2 mRNA and protein has now been shown to be decreased by the induction of p53 in Saos2 cells. Ionizing radiation also triggered the phosphorylation and subsequent down-regulation of Chk2 in human colorectal HCT116 (p53(+/+)) cancer cells; irradiation of its isogenic mutant HCT116 (p53(-/-)) cells, which lack functional p53, induced Chk2 phosphorylation but not its down-regulation. In addition, HCT116 (p53(+/+)) cells constitutively expressing a dominant negative p53 (V143A) failed to suppress Chk2 expression after irradiation. Reporter gene assays in HCT116 (p53(+/+)) cells revealed that wild-type p53 repressed, whereas a dominant negative p53 mutant increased, the activity of the human Chk2 gene promoter. Mutational analysis showed that a CCAAT box located between nucleotides -152 and -138 of the promoter was responsible for its negative regulation by p53. Electrophoretic mobility shift assays demonstrated that the transcription factor NF-Y binds to this CCAAT sequence. A dominant negative mutant of NF-YA abolished the effect of p53 on Chk2 promoter activity. These results suggest that p53 negatively regulates Chk2 gene transcription through modulation of NF-Y function and that this regulation may be important for reentry of cells into the cell cycle after DNA damage is repaired.
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PMID:Negative regulation of Chk2 expression by p53 is dependent on the CCAAT-binding transcription factor NF-Y. 1504 52

STI571 is the most innovative drug for the cure of Chronic Myeloid Leukemia. It inhibits, in fact, the disease causative event, the p210 bcr-abl tyrosine kinase, and addresses clonal myeloid progenitors to apoptotic death. Here, we demonstrated that STI571 also induces growth arrest by activating the Chk2-Cdc25A-Cdk2 axis, a pathway complementary to p53 in the activation of G(1)/S cell cycle checkpoint. In vitro exposure to STI571 of 32D murine myeloid progenitor cell clones transducing a temperature-sensitive p210 bcr-abl construct was associated with Chk2 phosphorylation and activation, Cdc25A degradation and persistent Cdk2 inhibitory phosphorylation, preventing, in turn, cell transition to and progression throughout the S phase of cell cycle. Chk2 and Cdc25A are both components of a complex network that integrates signals involved in regulated cell cycle progression, DNA repair and cell decision between life or death. Chk2 gene mutations or decreased expression, leading to its protein loss of function on Cdc25A target, and Cdc25A overexpression have been linked to poor prognosis of human cancers. In CML, they might further enhance the proliferative advantage and genomic instability of clonal myeloid progenitors featuring a class of poor prognosis patients eventually resistant to STI571.
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PMID:Chk2 drives late G1/early S phase arrest of clonal myeloid progenitors expressing the p210 BCR-ABL tyrosine kinase in response to STI571. 1504 68

Fusion between nonsynchronized cells leads to the formation of heterokarya which transiently activate Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 and enter the prophase of the cell cycle, where they arrest due to a loss of Cdk1/cyclin B1 activity, activate p53, disorganize centrosomes, and undergo apoptosis. Here, we show that the down regulation of Cdk1/cyclin B is secondary to the activation of the DNA structure checkpoint kinase Chk2. Thus, syncytia generated by the fusion of asynchronous HeLa cells contain elevated levels of active Chk2 but not Chk1. Chk2 bearing the activating phosphorylation on threonine-68 accumulates in BRCA1 nuclear bodies when the cells arrest at the G2/M boundary. Inhibition of Chk2 by transfection of a dominant-negative Chk2 mutant or a chemical inhibitor, debromohymenialdesine, stabilizes centrosomes, maintains high cyclin B1 levels, and allows for a prolonged activation of Cdk1. Under these conditions, multinuclear HeLa syncytia do not arrest at the G2/M boundary and rather enter mitotis and subsequently die during the metaphase of the cell cycle. This mitotic catastrophe is associated with the activation of the pro-apoptotic caspase-3. Inhibition of caspases allows the cells to go beyond the metaphase arrest, indicating that apoptosis is responsible for cell death by mitotic catastrophe. In another, completely different model of mitotic catastrophe, namely 14.3.3 sigma-deficient HCT116 colon carcinoma cells treated with doxorubicin, Chk2 activation was also found to be deficient as compared to 14.3.3 sigma-sufficient controls. Inhibition of Chk2 again facilitated the induction of mitotic catastrophe in HCT116 wild-type cells. In conclusion, a conflict in cell cycle progression or DNA damage can lead to mitotic catastrophe, provided that the checkpoint kinase Chk2 is inhibited. Inhibition of Chk2 thus can sensitize proliferating cells to chemotherapy-induced apoptosis.
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PMID:The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. 1504 74

A conflict in cell cycle progression or DNA damage can lead to mitotic catastrophe when the DNA structure checkpoints are inactivated, for instance when the checkpoint kinase Chk2 is inhibited. Here we show that in such conditions, cells die during the metaphase of the cell cycle, as a result of caspase activation and subsequent mitochondrial damage. Molecular ordering of these phenomena reveals that mitotic catastrophe occurs in a p53-independent manner and involves a primary activation of caspase-2, upstream of cytochrome c release, followed by caspase-3 activation and chromatin condensation. Suppression of caspase-2 by RNA interference or pseudosubstrate inhibitors as well as blockade of the mitochondrial membrane permeabilization prevent the mitotic catastrophe and allow cells to further proceed the cell cycle beyond the metaphase, leading to asymmetric cell division. Heterokarya generated by the fusion of nonsynchronized cells can be driven to divide into three or more daughter cells when Chk2 and caspases are simultaneously inhibited. Such multipolar divisions, resulting from suppressed mitotic catastrophe, lead to the asymmetric distribution of cytoplasm (anisocytosis), DNA (anisokaryosis) and chromosomes (aneuploidy). Similarly, in a model of DNA damage-induced mitotic catastrophe, suppression of apoptosis leads to the generation of aneuploid cells. Our findings delineate a molecular pathway through which DNA damage, failure to arrest the cell cycle and inhibition of apoptosis can favor the occurrence of cytogenetic abnormalities that are likely to participate in oncogenesis.
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PMID:Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy. 1504 75


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