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

A Cre/lox-conditional mouse line was generated to evaluate the role of ATR in checkpoint responses to ionizing radiation (IR) and stalled DNA replication. We demonstrate that after IR treatment, ATR and ATM each contribute to early delay in M-phase entry but that ATR regulates a majority of the late phase (2-9 h post-IR). Double deletion of ATR and ATM eliminates nearly all IR-induced delay, indicating that ATR and ATM cooperate in the IR-induced G2/M-phase checkpoint. In contrast to the IR-induced checkpoint, checkpoint delay in response to stalled DNA replication is intact in ATR knockout cells and ATR/ATM and ATR/p53 double-knockout cells. The DNA replication checkpoint remains intact in ATR knockout cells even though the checkpoint-stimulated inhibitory phosphorylation of Cdc2 on T14/Y15 and activating phosphorylation of the Chk1 kinase no longer occur. Thus, incomplete DNA replication in mammalian cells can prevent M-phase entry independently of ATR and inhibitory phosphorylation of Cdc2. When DNA replication inhibitors are removed, ATR knockout cells proceed to mitosis but do so with chromosome breaks, indicating that ATR provides a key genome maintenance function in S phase.
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PMID:Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. 1262 44

Cell cycle checkpoints are activated in response to DNA-damage to ensure that accurate copies of the cellular genome are passed on to the next generation and to avoid replication and segregation of damaged DNA. These cellular control systems can be overcome by combining conventional DNA-damaging agents with compounds that target the cell cycle regulatory pathways, to enhance cytotoxicity. Tumor cells often comprise a corrupted G(1) cell cycle checkpoint while the G(2) cell cycle checkpoint is still intact. This review describes the concept of G(2) checkpoint abrogation with recognized (methylxanthines, UCN-01) and novel G(2) checkpoint abrogators to potentiate the cytotoxicity of DNA-damaging drugs and ionizing radiation. It illustrates the potential of G(2) checkpoint abrogators to preferentially sensitize p53-mutated, treatment resistant tumor cells for genotoxic treatment. Identification of the targets of caffeine and UCN-01 to be key-players of the G(2) checkpoint (ATM/ATR and Chk1, respectively) promoted the search for novel inhibitors of this checkpoint. Even though a direct causal link between G(2) checkpoint abrogation and chemo-/radiosensitization is difficult to prove the multitude of these novel compounds validate that inhibition of critical elements of the G(2) checkpoint (ATM/ATR-Chk1/Chk2-CDC25C-cascade) potentiates the cytotoxicity of DNA-damaging agents.
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PMID:Potentiation of DNA-damage-induced cytotoxicity by G2 checkpoint abrogators. 1267 13

Eukaryotic cells control the initiation of DNA replication so that origins that have fired once in S phase do not fire a second time within the same cell cycle. Failure to exert this control leads to genetic instability. Here we investigate how rereplication is prevented in normal mammalian cells and how these mechanisms might be overcome during tumor progression. Overexpression of the replication initiation factors Cdt1 and Cdc6 along with cyclin A-cdk2 promotes rereplication in human cancer cells with inactive p53 but not in cells with functional p53. A subset of origins distributed throughout the genome refire within 2-4 hr of the first cycle of replication. Induction of rereplication activates p53 through the ATM/ATR/Chk2 DNA damage checkpoint pathways. p53 inhibits rereplication through the induction of the cdk2 inhibitor p21. Therefore, a p53-dependent checkpoint pathway is activated to suppress rereplication and promote genetic stability.
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PMID:A p53-dependent checkpoint pathway prevents rereplication. 1271 85

Nitric oxide (NO) is a potent activator of the p53 tumor suppressor protein. However, the mechanisms underlying p53 activation by NO have not been fully elucidated. We previously reported that a rapid downregulation of Mdm2 by NO may contribute to the early phase of p53 activation. Here we show that NO promotes p53 nuclear retention and inhibits Mdm2-mediated p53 nuclear export. NO induces phosphorylation of p53 on serine 15, which does not require ATM but rather appears to depend on the ATM-related ATR kinase. An ATR-kinase dead mutant or caffeine, which blocks the kinase activity of ATR, effectively abolishes the ability of NO to cause p53 nuclear retention, concomitant with its inhibition of p53 serine 15 phosphorylation. Of note, NO enhances markedly the ability of low-dose ionizing radiation to elicit apoptotic killing of neuroblastoma cells expressing cytoplasmic wild-type p53. These findings imply that, through augmenting p53 nuclear retention, NO can sensitize tumor cells to p53-dependent apoptosis. Thus, NO donors may potentially increase the efficacy of radiotherapy for treatment of certain types of cancer.
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PMID:Nitric oxide promotes p53 nuclear retention and sensitizes neuroblastoma cells to apoptosis by ionizing radiation. 1271 24

The ability of the conceptus to respond to genotoxic stress may be critical for normal development, particularly after exposure to genotoxic teratogens. Members of the phosphatidylinositol 3-kinase (PI3K) superfamily are involved in controlling cell cycle activity and maintaining genomic stability. The expression of PI3K family members ATM, ATR, and DNA-PKcs, and downstream genes p53, GADD45, and p21, was examined in the mid organogenesis rat conceptus in vivo on gestational days (GD) 10 through 12 and in vitro following exposure to genotoxic stress. ATM was the most highly expressed PI3K family member in both yolk sac and embryo proper, with transcript levels increasing ~fourfold in the embryo from GD 10 to 12. Transcript concentrations for ATR, DNA-PKcs, and downstream genes were low in both tissues; all genes had increased transcript levels exclusively in the GD 12 embryo. Transient oxidative stress, induced by short-term, in vitro embryo culture, had no effect on transcript levels in either tissue. Culture for 24 or 44 h significantly decreased ATM transcript levels in both embryo and yolk sac, but downstream genes were unaffected compared to GD-11 and -12 in vivo levels, respectively. Exposure to 4-hydroperoxycyclophosphamide (4-OOHCPA), an activated form of the nitrogen mustard cyclophosphamide (CPA), had no effect on transcript levels for any of the genes examined. Therefore, while transcripts for genotoxic stress-response genes are present in the mid organogenesis rat conceptus, their expression is not regulated by exposure in culture to either transient oxidative stress or a genotoxic alkylating agent. The inability of the conceptus to upregulate transcripts in response to insult may contribute to an increased susceptibility to stressors during organogenesis.
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PMID:Genotoxic stress response gene expression in the mid-organogenesis rat conceptus. 1273 Jun 23

Topoisomerase inhibitors are among the most efficient inducers of apoptosis. The main pathways leading from topoisomerase-mediated DNA damage to cell death involve activation of caspases in the cytoplasm by proapoptotic molecules released from mitochondria. In some cells, apoptotic response also involves the death receptor Fas (APO-1/CD95). The engagement of these apoptotic effector pathways is tightly controlled by upstream regulatory pathways that respond to DNA lesions-induced by topoisomerase inhibitors in cells undergoing apoptosis. These include the proapoptotic Chk2, c-Abl and SAPK/JNK pathways, the survival PI(3)kinase-Akt-dependent pathway and the transcription factors p53 and NF-kappaB. Initiation of cellular responses to DNA lesions-induced by topoisomerase inhibitors is ensured by the protein kinases DNA-PK, ATM and ATR, which bind to DNA breaks. These kinases commonly called "DNA sensors" mediate their effects (DNA repair, cell cycle arrest and/or apoptosis) by phosphorylating a large number of substrates, including several downstream kinases such as c-Abl and the checkpoint protein Chk2. c-Abl induces apoptosis by activating cell death pathways (e.g., SAPK, p53 and p73) and inhibiting cell survival pathways [e.g., PI(3)kinase]. The DNA-damage regulating kinase Chk2, in addition to its role in cell cycle arrest and/or DNA repair, can induce apoptosis by phosphorylation/activation of the promyelocytic leukemia (PML) protein and p53. Finally, we will review the recent observations that support a role for topoisomerases in chromatin fragmentation during the execution phase of apoptosis.
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PMID:Apoptosis induced by topoisomerase inhibitors. 1276 73

BRCA1 is a central component of the DNA damage response mechanism and defects in BRCA1 confer sensitivity to a broad range of DNA damaging agents. BRCA1 is required for homologous recombination and DNA damage-induced S and G(2)/M phase arrest. We show here that BRCA1 is required for ATM- and ATR-dependent phosphorylation of p53, c-Jun, Nbs1 and Chk2 following exposure to ionizing or ultraviolet radiation, respectively, and is also required for ATM phosphorylation of CtIP. In contrast, DNA damage-induced phosphorylation of the histone variant H2AX is independent of BRCA1. We also show that the presence of BRCA1 is dispensable for DNA damage-induced phosphorylation of Rad9, Hus1 and Rad17, and for the relocalization of Rad9 and Hus1. We propose that BRCA1 facilitates the ability of ATM and ATR to phosphorylate downstream substrates that directly influence cell cycle checkpoint arrest and apoptosis, but that BRCA1 is dispensable for the phosphorylation of DNA-associated ATM and ATR substrates.
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PMID:A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. 1277

2-Aminopurine (2-AP) is an adenine analog shown to cause cells to bypass chemical- and radiation-induced cell cycle arrest through as-yet unidentified mechanisms. 2-AP has also been shown to act as a kinase inhibitor. Tumor suppressor p53 plays an important role in the control of cell cycle and apoptosis in response to genotoxic stress. We were interested in examining the effect of 2-AP on p53 phosphorylation and its possible consequences on checkpoint control in cells subjected to various forms of DNA damage. Here, we show that 2-AP suppresses p53 phosphorylation in response to gamma radiation, adriamycin, or ultraviolet treatment. This is partly explained by the ability of the kinase inhibitor to inhibit ATM or ATR activities in vitro and impair ATM- or ATR-dependent p53 phosphorylation in vivo. However, 2-AP is also capable of inhibiting p53 phosphorylation in cells deficient in ATM, DNA-PK, or ATR suggesting the existence of multiple pathways by which this kinase inhibitor modulates p53 activation. Biologically, the 2-AP-mediated inhibition of p53 stabilization enables wild-type p53-containing cells to bypass adriamycin-induced G(2)/M arrest. In the long term, however, 2-AP facilitates cells to resist DNA damage-induced cell death independently of p53.
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PMID:Protein kinase inhibitor 2-aminopurine overrides multiple genotoxic stress-induced cellular pathways to promote cell survival. 1280 79

p19ARF is induced in response to oncogene activation or during cellular senescence in mouse embryo fibroblasts, triggering p53-dependent and p53-independent cell cycle arrest and apoptosis. We have studied the involvement of human p14ARF as a regulator of p53 activity in normal human skin fibroblasts (NHFs) or WI38 lung embryonic fibroblasts expressing conditional Myc or E2F1 estrogen receptor fusion proteins. Both Myc and E2F1 activation rapidly induced p53 phosphorylation at Ser-15, p53 protein accumulation, and upregulation of the p53 target genes MDM2 and p21. Activation of E2F1 induced p14ARF mRNA and protein levels. In contrast, Myc activation did not induce any significant increase in p14ARF mRNA or protein levels in neither NHFs nor WI38 fibroblasts within 48 h. Myc and E2F1 induced p53 and cell cycle arrest even after silencing of p14ARF using short-interfering RNA. Treatment with the ATM/ATR kinase inhibitor caffeine prevented p53 accumulation upon activation of Myc or E2F1. Our results indicate that p53 phosphorylation, but not p14ARF, plays a major role for the induction of p53 in response to Myc and E2F1 activation in normal human fibroblasts.
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PMID:Myc and E2F1 induce p53 through p14ARF-independent mechanisms in human fibroblasts. 1290 82

Damage induced in the DNA after exposure of cells to ionizing radiation activates checkpoint pathways that inhibit progression of cells through the G1 and G2 phases and induce a transient delay in the progression through S phase. Checkpoints together with repair and apoptosis are integrated in a circuitry that determines the ultimate response of a cell to DNA damage. Checkpoint activation typically requires sensors and mediators of DNA damage, signal transducers and effectors. Here, we review the current state of knowledge regarding mechanisms of checkpoint activation and proteins involved in the different steps of the process. Emphasis is placed on the role of ATM and ATR, as well on CHK1 and CHK2 kinases in checkpoint response. The roles of downstream effectors, such as P53 and the CDC25 family of proteins, are also described, and connections between repair and checkpoint activation are attempted. The role of checkpoints in genomic stability and the potential of improving the treatment of cancer by DNA damage inducing agents through checkpoint abrogation are also briefly outlined.
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PMID:DNA damage checkpoint control in cells exposed to ionizing radiation. 1294 90


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