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)

Functional inactivation of the p53 gene and robust DNA repair capacity may be among the salient causes of radioresistance in tumor cells. We expressed the wild-type (wt) p53 gene in a p53-mutant human epidermoid carcinoma cell line, A431, using an adenoviral vector [adenovirus-p53 (Ad-p53), INGN 201], examined its radiosensitivity, and correlated p53 status and radiosensitivity with cellular repair functions. Using clonogenic survival assays and the terminal deoxynucleotidyl transferase-mediated nick end labeling assay for apoptosis, we demonstrated that preirradiation treatment with Ad-p53 significantly increased the radiosensitivity of A431 cells over controls. Induction of p53 expression using a construct where p53 expression was under the control of an inducible promoter also significantly increased radiosensitivity of H1299 lung tumor cells, which are otherwise null for p53. These results did not correlate with radiation-induced apoptosis but did correlate with functional impairment of DNA repair and suppressed expression of several repair-related genes, such as Ku70, DNA-dependent protein kinase, ataxia telangiectasia mutated, and X-ray-sensitive complementation group 4. Normal human fibroblast MRC-9 cells showed no impairment in the repair capability due to Ad-p53 despite the suppression of some repair genes. Expression of Ku70, which is known to mediate diverse cellular functions, correlated with the differential effects of p53 on radiosensitivity in the normal and tumor cells.
 ...
PMID:Adenovirus-mediated wild-type p53 radiosensitizes human tumor cells by suppressing DNA repair capacity. 1461 96

We have identified a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor kappaB (NF-kappaB) activation and chemoresistance in response to DNA damage. We show that the anthracycline doxorubicin (DOX) and its congener N-benzyladriamycin (AD 288) selectively activate ATM and DNA-PK, respectively. Both ATM and DNA-PK promote sequential activation of the mitogen-activated protein kinase (MAPK)/p90(rsk) signaling cascade in a p53-independent fashion. In turn, p90(rsk) interacts with the IkappaB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-kappaB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-kappaB pathway that opposes the apoptotic response following DNA damage.
 ...
PMID:ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-kappaB through a common MEK/extracellular signal-regulated kinase/p90(rsk) signaling pathway in response to distinct forms of DNA damage. 1496 65

The complex containing the Mre11, Rad50, and Nbs1 proteins (MRN) is essential for the cellular response to DNA double-strand breaks, integrating DNA repair with the activation of checkpoint signaling through the protein kinase ATM (ataxia telangiectasia mutated). We demonstrate that MRN stimulates the kinase activity of ATM in vitro toward its substrates p53, Chk2, and histone H2AX. MRN makes multiple contacts with ATM and appears to stimulate ATM activity by facilitating the stable binding of substrates. Phosphorylation of Nbs1 is critical for MRN stimulation of ATM activity toward Chk2, but not p53. Kinase-deficient ATM inhibits wild-type ATM phosphorylation of Chk2, consistent with the dominant-negative effect of kinase-deficient ATM in vivo.
 ...
PMID:Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. 1506 16

Screening of expression libraries for bioactive clones that modulate the growth of mammalian cells has been limited largely to positive selections incapable of revealing growth suppressive or lethal genetic elements. We have developed a technique, selection-subtraction approach (SSA), that allows growth-modulating clones to be isolated based on alterations in their relative abundance in growing cell populations that have been transduced with an expression library. SSA utilizes tagged retroviral libraries in bacteriophage lambda vectors (retrophages). Nylon prints from retrophage libraries are used to determine the relative abundance of tags in library-transduced cells to identify biological activity of individual clones. Applications of SSA for gene discovery, target discovery, and generation of mutant proteins have been demonstrated, by using p53 and ataxia telangiectasia mutated (ATM) as models to isolate growth inhibitory proteins, peptides and antisense RNAs, and temperature-sensitive mutant proteins.
 ...
PMID:Selection-subtraction approach (SSA): a universal genetic screening technique that enables negative selection. 1518 33

Phosphorylation at multiple sites within the N-terminus of p53 promotes its dissociation from hdm2/mdm2 and stimulates its transcriptional regulatory potential. The large phosphoinositide 3-kinase-like kinases ataxia telangiectasia mutated gene product and the ataxia telangectasia and RAD-3-related kinase promote phosphorylation of human p53 at Ser15 and Ser20, and are required for the activation of p53 following DNA damage. DNA-dependent protein kinase (DNA-PK) is another large phosphoinositide 3-kinase-like kinase with the potential to phosphorylate p53 at Ser15, and has been proposed to enhance phosphorylation of these sites in vivo. Moreover, recent studies support a role for DNA-PK in the regulation of p53-mediated apoptosis. We have shown previously that colocalization of p53 and DNA-PK to structured single-stranded DNA dramatically enhances the potential for p53 phosphorylation by DNA-PK. We report here the identification of p53 phosphorylation at two novel sites for DNA-PK, Thr18 and Ser9. Colocalization of p53 and DNA-PK on structured DNA was required for efficient phosphorylation of p53 at multiple sites, while specific recognition of Ser9 and Thr18 appeared to be dependent upon additional determinants of p53 beyond the N-terminal 65 amino acids. Our results suggest a role for DNA-PK in the modulation of p53 activity resultant from the convergence of p53 and DNA-PK on structured DNA.
 ...
PMID:Structured DNA promotes phosphorylation of p53 by DNA-dependent protein kinase at serine 9 and threonine 18. 1535 54

Exceptional progress has been made in the past two decades in mapping oncogenes and tumour suppressors, defining a function for these master switches, and identifying novel anti-cancer drug targets. The p53 tumour suppressor is a central component of a DNA-damage-inducible pathway controlled by the ataxia telangiectasia mutated (ATM) and CHK2 protein kinases that have a central role in cancer suppression. One limitation of current human cancer research is the difficulty in developing genetic models that reveal the post-translational regulation of a growth suppressor like CHK2 within the microenvironment of a human tumour. Gaining such insights is important since yeast models and human tissue culture cell lines do not necessarily predict how enzymes like CHK2 are regulated in vivo, and therefore what factors can affect CHK2 tumour suppressor function. Translational cancer research aims to link basic research methodologies and clinical biology by uncovering cancer-specific pathways not revealed by other approaches. This approach is exemplified by two studies in this edition of Oncogene: both use a set of well-characterized human cancers with the objective of identifying novel post-translational control of the tumour suppressor CHK2. The authors have revealed two unexpected epigenetic modifications of the CHK2 pathway in vivo: (1) constitutive phosphorylation of CHK2 at its ATM-activated site in the absence of exogenous DNA damage; and (2) the production of hyper-spliced and inactive isoforms of CHK2. These studies highlight the need to develop model systems to understand why CHK2-activating pathways are being triggered or suppressed in different human cancers and whether the splicing machinery can be manipulated to control the activity of CHK2 for therapeutic benefit.
 ...
PMID:The regulation of CHK2 in human cancer. 1536 53

The ataxia telangiectasia mutated (ATM) and ATR (ATM and Rad3-related) protein kinases exert cell cycle delay, in part, by phosphorylating Checkpoint kinase (Chk) 1, Chk2, and p53. It is well established that ATR is activated following UV light-induced DNA damage such as pyrimidine dimers and the 6-(1,2)-dihydro-2-oxo-4-pyrimidinyl-5-methyl-2,4-(1H,3H)-pyrimidinediones, whereas ATM is activated in response to double strand DNA breaks. Here we clarify the activation of these kinases in cells exposed to IR, UV, and hyperoxia, a condition of chronic oxidative stress resulting in clastogenic DNA damage. Phosphorylation on Chk1(Ser-345), Chk2(Thr-68), and p53(Ser-15) following oxidative damage by IR involved both ATM and ATR. In response to ultraviolet radiation-induced stalled replication forks, phosphorylation on Chk1 and p53 required ATR, whereas Chk2 required ATM. Cells exposed to hyperoxia exhibited growth delay in G1, S, and G2 that was disrupted by wortmannin. Consistent with ATM or ATR activation, hyperoxia induced wortmannin-sensitive phosphorylation of Chk1, Chk2, and p53. By using ATM- and ATR-defective cells, phosphorylation on Chk1, Chk2, and p53 was found to be ATM-dependent, whereas ATR also contributed to Chk1 phosphorylation. These data reveal activated ATM and ATR exhibit selective substrate specificity in response to different genotoxic agents.
 ...
PMID:Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage. 1553 33

Ten new patients with ataxia telangiectasia-like disorder (ATLD) from three unrelated Saudi Arabian families have been identified aged 5-37 representing the largest cohort of ATLD patients ever identified. They presented with an early-onset, slowly progressive, ataxia plus ocular apraxia phenotype with an absence of tumor development, even in the oldest patient. Extra-neurological features such as telangiectasia, raised alpha-fetoprotein and reduced immunoglobulin levels were absent. No translocations were found in the two investigated patients, and the presence of microcephaly was noted in four out of eight ascertained patients. All patients are homozygous for a novel missense mutation (630G-->C, W210C) of the MRE11 gene. The cellular consequences of this amino acid change, localized in the nuclease domain of the Mre11 protein, have been determined in fibroblast cultures established from two individuals. They showed high constitutive levels of Mre11 and Rad50 proteins compared with cells from normal individuals but a very low level of the Nbs1 protein. After exposure to ionizing radiation, a dose-dependent defect in ataxia telangiectasia mutated (ATM)-serine 1981, p53-serine 15 and Chk2 phosphorylation, and p53 stabilization were noted, together with a failure to form Mre11 foci and enhanced radiation sensitivity. Formation of gammaH2AX foci was similar to that seen in normal fibroblasts under the experimental conditions examined. These results emphasize the importance of functional interactions among the three proteins of the Mre11-Rad50-Nbs1 complex and lend support to a role of this complex as a sensor of DNA double-strand breaks, acting upstream of ATM.
 ...
PMID:Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. 1557 63

We studied the interactions between human herpesvirus 6B (HHV-6B) and its host cell. Productive infections of T-cell lines led to G1/S- and G2/M-phase arrest in the cell cycle concomitant with an increased level and enhanced DNA-binding activity of p53. More than 70% of HHV-6B-infected cells did not bind annexin V, indicating that the majority of cells were not undergoing apoptosis. HHV-6B infection induced Ser20 and Ser15 phosphorylation on p53, and the latter was inhibited by caffeine, an ataxia telangiectasia mutated kinase inhibitor. Thus, a productive HHV-6B infection suppresses T-cell proliferation concomitant with the phosphorylation and accumulation of p53.
 ...
PMID:Human herpesvirus 6B induces cell cycle arrest concomitant with p53 phosphorylation and accumulation in T cells. 1565 Feb 24

Friend leukemia virus (FLV) infection strongly enhances gamma-irradiation-induced apoptosis of hematopoietic cells of C3H hosts leading to a lethal anemia. Experiments using p53 knockout mice with the C3H background have clarified that the apoptosis is p53-dependent and would not be associated with changes of cell populations caused by the infection with FLV. In bone marrow cells of FLV + total body irradiation (TBI)-treated C3H mice, the p53 protein was prominently activated to overexpress p21 and bax suggesting that apoptosis-enhancing mechanisms lay upstream of p53 protein in the signaling pathway. Neither of DNA-dependent protein kinase (DNA-PK)-deficient SCID mice nor ataxia telangiectasia mutated (ATM) gene knockout mice with the C3H background exhibited a remarkable enhancement of apoptosis or p53 activation on FLV + TBI-treatment indicating that DNA-PK and ATM were both essential. ATM appeared necessary for introducing DNA damage-induced apoptosis, while DNA-PK enhanced p53-dependent apoptosis under FLV-infection. Surprisingly, viral envelope protein, gp70, was co-precipitated with DNA-PK but not with ATM in FLV + TBI-treated C3H mice. These results indicated that FLV-infection enhances DNA damage-induced apoptosis via p53 activation and that DNA-PK, in association with gp70, might play critical roles in modulating the signaling pathway.
 ...
PMID:DNA-dependent protein kinase enhances DNA damage-induced apoptosis in association with Friend gp70. 1566 Dec 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>