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)

Commonly used antitumor agents, such as DNA topoisomerase I/II poisons, kill cancer cells by creating nonrepairable DNA double-strand breaks (DSBs). To repair DSBs, error-free homologous recombination (HR), and/or error-prone nonhomologous end joining (NHEJ) are activated. These processes involve the phosphatidylinositol 3'-kinase-related kinase family of serine/threonine enzymes: ataxia telangiectasia mutated (ATM), ATM- and Rad3-related for HR, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) for NHEJ. Alterations in these repair processes can cause drug/radiation resistance and increased genomic instability. beta-Lapachone (beta-lap; also known as ARQ 501), currently in phase II clinical trials for the treatment of pancreatic cancer, causes a novel caspase- and p53-independent cell death in cancer cells overexpressing NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 catalyzes a futile oxidoreduction of beta-lap leading to reactive oxygen species generation, DNA breaks, gamma-H2AX foci formation, and hyperactivation of poly(ADP-ribose) polymerase-1, which is required for cell death. Here, we report that beta-lap exposure results in NQO1-dependent activation of the MRE11-Rad50-Nbs-1 complex. In addition, ATM serine 1981, DNA-PKcs threonine 2609, and Chk1 serine 345 phosphorylation were noted; indicative of simultaneous HR and NHEJ activation. However, inhibition of NHEJ, but not HR, by genetic or chemical means potentiated beta-lap lethality. These studies give insight into the mechanism by which beta-lap radiosensitizes cancer cells and suggest that NHEJ is a potent target for enhancing the therapeutic efficacy of beta-lap alone or in combination with other agents in cancer cells that express elevated NQO1 levels.
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PMID:Nonhomologous end joining is essential for cellular resistance to the novel antitumor agent, beta-lapachone. 1763 5

In this study we investigated the involvement of p53 in cytotoxic T-lymphocyte (CTL)-induced tumor target cell killing mediated by the perforin/granzymes pathway. For this purpose we used a human CTL clone (LT12) that kills its autologous melanoma target cells (T1), harboring a wild type p53. We demonstrated initially that LT12 kills its T1 target in a perforin/granzymes-dependent manner. Confocal microscopy and Western blot analysis indicated that conjugate formed between LT12 and T1 resulted in rapid cytoplasmic accumulation of p53 and its activation in T1 target cells. Cytotoxic assay using recombinant granzyme B (GrB) showed that this serine protease is the predominant factor inducing such accumulation. Furthermore, RNA interference-mediated lowering of the p53 protein in T1 cells or pifithrin-alpha-induced p53-specific inhibition activity significantly decreased CTL-induced target killing mediated by CTL or recombinant GrB. This emphasizes that p53 is an important determinant in granzyme B-induced apoptosis. Our data show furthermore that when T1 cells were treated with streptolysin-O/granzyme B, specific phosphorylation of p53 at Ser-15 and Ser-37 residues was observed subsequent to the activation of the stress kinases ataxia telangiectasia mutated (ATM) and p38K. Treatment of T1 cells with pifithrin-alpha resulted in inhibition of p53 phosphorylation at these residues and in a significant decrease in GrB-induced apoptotic T1 cell death. Furthermore, small interference RNAs targeting p53 was also accompanied by an inhibition of streptolysin-O/granzyme B-induced apoptotic T1 cell death. The present study supports p53 induction after CTL-induced stress in target cells. These findings provide new insight into a potential role of p53 as a component involved in the dynamic regulation of the major pathway of CTL-mediated cell death and may have therapeutic implications.
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PMID:Granzyme B-induced cell death involves induction of p53 tumor suppressor gene and its activation in tumor target cells. 1785 37

gamma-Irradiation-mediated ataxia telangiectasia mutated (ATM)-dependent dephosphorylation of serine 376 (S376) at the carboxyl terminus of human p53 results in the exposure of the 14-3-3 consensus-binding site, which includes serine 378 (S378). 14-3-3 binding potentiates p53's DNA-binding ability and causes G(1) arrest. Moreover,endoplasmic reticulum stress-mediated S376 phosphorylation was shown to localize human p53 in the cytoplasm. Although many functions are conserved between human and mouse p53, the functional relevance of S376 and S378 mouse equivalents is not clear. We report here that gamma-irradiation does not lead to 14-3-3 binding to mouse p53. Mouse p53 mutants, such as S373A/D (the equivalent of human S376), S375A/D (the equivalent of human S378), and combinatorial double mutants, were not impaired in their ability to transactivate p53-dependent target genes and were capable of inducing G(1) arrest as efficiently as wild-type p53. Consistently, all mutant p53s were as potent as wild-type mouse p53 in inhibiting cellular colony formation. Furthermore, mouse S373A/D mutants were not defective in cytoplasmic localization in response to endoplasmic reticulum stress. Together, the data suggest that despite a high homology with human p53, neither phosphorylation status at S373 and S375 nor 14-3-3 binding may be a critical event for mouse p53 to be functional.
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PMID:Phosphorylation at carboxyl-terminal S373 and S375 residues and 14-3-3 binding are not required for mouse p53 function. 1789 64

In chronic lymphocytic leukaemia (CLL), mutation/deletion of TP53 is strongly associated with early disease progression, resistance to chemotherapy and short patient survival. Consequently, there is a pressing need to develop novel treatment protocols for this high-risk patient group. The present study was performed to evaluate Hsp90 inhibition as a possible therapeutic approach for such patients. Primary CLL cells of defined ataxia telangiectasia mutated (ATM)/p53 status were incubated with the Hsp90 inhibitor geldanamycin (GA) and analysed by western blotting for the expression of p53, p21, MDM2 and Akt. GA downregulated overexpressed mutant p53 protein (an oncogene) and upregulated wild-type (wt) p53 (a tumour suppressor). The upregulation of wt p53 by GA was independent of ATM and was accompanied by downregulation of Akt and the active form of MDM2, indicating a possible mechanism. GA also produced a p53/ATM-independent increase in the levels of p21-a potent inducer of cell-cycle arrest. In-vitro cytotoxicity studies showed that GA killed cultured CLL cells in a dose- and time-dependent fashion irrespective of their p53/ATM status and more effectively than normal blood mononuclear cells. In summary, our findings reveal important consequences of inhibiting Hsp90 in CLL cells and strongly support the therapeutic evaluation of Hsp90 inhibitors in poor-prognosis patients with p53 defects.
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PMID:Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells. 1798 89

Chemotherapeutic drugs such as fludarabine*, doxorubicin or cisplatin are very potent activators of the anti-oncogene p53. Convergent studies suggest that p53 and STAT1 (signal transducer and activator of transcription 1) cooperate in the induction of cell death. We show that these drugs are also activators of STAT1 in p53-expressing cells, but not in p53-null cells. STAT1 activation was obtained in the presence of both the secretion inhibitor brefeldine A and the inhibitor of RNA synthesis, actinomycin D. p53-dependent STAT1 activation was reversed by overexpression of MDM2 and siRNAs against p53. Genetic analysis of p53 showed that expression of transcriptionally inactive p53 punctual mutants markedly increased Y701-STAT1 phosphorylation, and suggests that the p53 DNA-binding domain was alternatively involved in STAT1 activation or p53 multimerization. Immunoprecipitation experiments showed that ataxia telangiectasia mutated, p53, STAT1 and c-Abl1 (Abelson murine leukaemia viral oncogene homologue 1) were associated together. Treatment of cells with the c-Abl1 tyrosine kinase inhibitor STI571 decreased STAT1 activation by genotoxic drugs. Finally, genotoxic agents sensitized cells in response to very low doses of both interferon alpha and gamma (IFNalpha and gamma). These results show that genotoxic drugs induce STAT1 activation, an effect that depends on p53 protein but not on p53 transcriptional activity, and point to a novel pathway of STAT1 activation by genotoxic drugs, with involvement of c-Abl1 tyrosine kinase in sensitizing cells to IFN response.
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PMID:Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents. 1799 89

Apoptotic cell death is initiated by a morphologically homogenous entity that was considered to be non-immunogenic and non-inflammatory in nature. However, recent advances suggest that apoptosis, under certain circumstances, can be immunogenic. In particular, some characteristics of the plasma membrane, acquired at preapoptotic stage, can cause immune effectors to recognize and attack preapoptotic tumor cells. The signals that mediate the immunogenicity of tumor cells involve elements of the DNA damage response (such as ataxia telangiectasia mutated and p53 activation), elements of the endoplasmic reticulum stress response (such as eukaryotic initiation factor 2alpha phosphorylation), as well as elements of the apoptotic response (such as caspase activation). Depending on the signal-transduction pathway, tumor cells responding to chemotherapy or radiotherapy can express 'danger' and 'eat me' signals on the cell surface (such as NKG2D ligands, heat-shock proteins and calreticulin) or can secrete/release immunostimulatory factors (such as cytokines and high-mobility group box 1) to stimulate innate immune effectors. Likewise, the precise sequence of such events influences the 'decision' of the immune system to mount a cognate response or not. We therefore anticipate that the comprehension of the mechanisms governing the immunogenicity of cell death will have a profound impact on the design of anticancer therapies.
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PMID:Molecular characteristics of immunogenic cancer cell death. 1800 63

Cisplatin is one of the most effective and widely used chemotherapeutic agents. However, one of the most salient limitations to the clinical application of cisplatin is the acquired or intrinsic drug resistance exhibited by some tumors. In the present study, we have assessed the potential of an intracellular energy balancing system as a target for augmentation of cisplatin sensitivity in tumors. AMP-activated protein kinase (AMPK) regulates the energy balance system by monitoring intracellular energy status. Here we demonstrate that AMPK is rapidly activated by cisplatin in AGS and HCT116 cancer cells. The inhibition of AMPK in those cells and in xenografts of HCT116 resulted in a remarkable increase in cisplatin-induced apoptosis, which was associated with hyper-induction of the tumor suppressor p53. We further showed that ERK, but not ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) kinases, was involved in the hyper-induction of p53 by the inhibition of cisplatin-induced AMPK. By way of contrast, cisplatin did not induce AMPK activation in HeLa cells, which appear to have a relatively high sensitivity to cisplatin-induced cytotoxicity, but expression of the constitutive active form of AMPK in HeLa cells resulted in a significant increase of cell viability after cisplatin treatment. Collectively, our data suggest that AMPK performs a pivotal function for protection against the cytotoxic effect of cisplatin, thereby implying that AMPK is one of the cellular factors determining the cellular sensitivity to cisplatin. On the basis of these observations, we propose that a strategy combining cisplatin and AMPK inhibition could be developed into a novel chemotherapeutic modality.
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PMID:Inhibition of AMP-activated protein kinase sensitizes cancer cells to cisplatin-induced apoptosis via hyper-induction of p53. 3044 5

PR-Set7/SET8 is a histone H4-lysine 20 methyltransferase required for normal cell proliferation. However, the exact functions of this enzyme remain to be determined. In this study, we show that human PR-Set7 functions during S phase to regulate cellular proliferation. PR-Set7 associates with replication foci and maintains the bulk of H4-K20 mono- and trimethylation. Consistent with a function in chromosome dynamics during S phase, inhibition of PR-Set7 methyltransferase activity by small hairpin RNA causes a replicative stress characterized by alterations in replication fork velocity and origin firing. This stress is accompanied by massive induction of DNA strand breaks followed by a robust DNA damage response. The DNA damage response includes the activation of ataxia telangiectasia mutated and ataxia telangiectasia related kinase-mediated pathways, which, in turn, leads to p53-mediated growth arrest to avoid aberrant chromosome behavior after improper DNA replication. Collectively, these data indicate that PR-Set7-dependent lysine methylation during S phase is an essential posttranslational mechanism that ensures genome replication and stability.
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PMID:PR-Set7-dependent lysine methylation ensures genome replication and stability through S phase. 1815 31

Cisplatin is one of the most effective anti-cancer drugs; however, the use of cisplatin is limited by its toxicity in normal tissues, particularly injury of the kidneys. The mechanisms underlying the therapeutic effects of cisplatin in cancers and side effects in normal tissues are largely unclear. Recent work has suggested a role for p53 in cisplatin-induced renal cell apoptosis and kidney injury; however, the signaling pathway leading to p53 activation and renal apoptosis is unknown. Here we demonstrate an early DNA damage response during cisplatin treatment of renal cells and tissues. Importantly, in the DNA damage response, we demonstrate a critical role for ATR, but not ATM (ataxia telangiectasia mutated) or DNA-PK (DNA-dependent protein kinase), in cisplatin-induced p53 activation and apoptosis. We show that ATR is specifically activated during cisplatin treatment and co-localizes with H2AX, forming nuclear foci at the site of DNA damage. Blockade of ATR with a dominant-negative mutant inhibits cisplatin-induced p53 activation and renal cell apoptosis. Consistently, cisplatin-induced p53 activation and apoptosis are suppressed in ATR-deficient fibroblasts. Downstream of ATR, both Chk1 and Chk2 are phosphorylated during cisplatin treatment in an ATR-dependent manner. Interestingly, following phosphorylation, Chk1 is degraded via the proteosomal pathway, whereas Chk2 is activated. Inhibition of Chk2 by a dominant-negative mutant or gene deficiency attenuates cisplatin-induced p53 activation and apoptosis. In vivo in C57BL/6 mice, ATR and Chk2 are activated in renal tissues following cisplatin treatment. Together, the results suggest an important role for the DNA damage response mediated by ATR-Chk2 in p53 activation and renal cell apoptosis during cisplatin nephrotoxicity.
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PMID:ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. 1816 65

The phytochemical resveratrol (RV) has become a focus of intense research owing to its roles in promoting longevity and in cancer prevention. As an anticancer agent, RV has primarily been linked to growth and death regulatory pathways. There is now growing evidence that, under physiological conditions, RV additionally contributes to the maintenance of genome stability. Thus, at the stage of DNA damage formation, RV protects the genome as an antioxidant via inhibition of inflammation, suppression of metabolic carcinogen activation, de novo expression of genes that encode detoxifying proteins and possibly even via radical scavenging properties. However, results demonstrating RV-dependent DNA breakage in the presence of Cu(II) ions and inhibition of DNA polymerases alpha and delta produced some controversy regarding RV's role as a caretaker compound. Significantly, recent studies have revealed that activation of ataxia telangiectasia mutated and ataxia telangiectasia Rad3 related could be a central effect of RV that underlies cell-cycle regulation and the newly described activation of fidelity control mechanisms in DNA double-strand break repair involving Nbs1 and p53. In this review, we discuss the existing data on RV's direct and indirect effects on genome integrity, in the light of future chemopreventive and chemotherapeutic protocols involving RV or related compounds.
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PMID:Take a break--resveratrol in action on DNA. 1817 51


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