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)

Although genotoxic agents are powerful inducers of stress kinases (SAPK/JNK), the contribution of DNA damage itself to this response is unknown. Therefore, SAPK/JNK activation of cells harboring specific defects in DNA damage-recognition mechanisms was studied. Dual phosphorylation of SAPK/JNK by the genotoxin methyl methanesulfonate (MMS) occurred in two waves. The early response (< or = 2 h after exposure) was similar in cells knockout for ATM, PARP, p53, and CSB or defective in DNA-PK(cs) compared with wild-type cells. The late response however (> or = 4 h), was drastically reduced in DNA-PK(cs) and Cockayne's syndrome B (CSB)-deficient cells. Similar results were obtained with human cells lacking DNA-PK(cs) and CSB. Activation of SAPK/JNK by MMS was not affected upon inhibition of base excision repair (BER), indicating base damage itself does not signal to SAPK/JNK. Because SAPK/JNK activation was attenuated in nongrowing cells, DNA replication-dependent processing of lesions, involving DNA-PK(cs) and CSB, appears to be required. DNA-PK(cs) coprecipitates with SEK1/MKK4 and SAPK/JNK, supporting a role of DNA-PK(cs) in SAPK/JNK activation. In this process, Rho GTPases are involved since inhibition of Rho impairs MMS-induced signaling to SAPK/JNK. The data show that sensing of DNA damage by DNA-PK(cs) and CSB causes a delayed SEK1/MKK4-mediated dual phosphorylation of SAPK/JNK.
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PMID:Late activation of stress kinases (SAPK/JNK) by genotoxins requires the DNA repair proteins DNA-PKcs and CSB. 1631 74

Rev3L encodes the catalytic subunit of DNA polymerase zeta (pol zeta) in mammalian cells. In yeast, pol zeta helps cells bypass sites of DNA damage that can block replication enzymes. Targeted disruption of the mouse Rev3L gene causes lethality midway through embryonic gestation, and Rev3L-/- mouse embryonic fibroblasts (MEFs) remain in a quiescent state in culture. This suggests that pol zeta may be necessary for tolerance of endogenous DNA damage during normal cell growth. We report the generation of mitotically active Rev3L-/- MEFs on a p53-/- genetic background. Rev3L null MEFs exhibited striking chromosomal instability, with a large increase in translocation frequency. Many complex genetic aberrations were found only in Rev3L null cells. Rev3L null cells had increased chromosome numbers, most commonly near pentaploid, and double minute chromosomes were frequently found. This chromosomal instability associated with loss of a DNA polymerase activity in mammalian cells is similar to the instability associated with loss of homologous recombination capacity. Rev3L null MEFs were also moderately sensitive to mitomycin C, methyl methanesulfonate, and UV and gamma-radiation, indicating that mammalian pol zeta helps cells tolerate diverse types of DNA damage. The increased occurrence of chromosomal translocations in Rev3L-/- MEFs suggests that loss of Rev3L expression could contribute to genome instability during neoplastic transformation and progression.
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PMID:Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. 1639 25

Oxidative stress and certain environmental carcinogens, e.g. vinyl chloride and its metabolite chloroacetaldehyde (CAA), introduce promutagenic exocyclic adducts into DNA, among them 1,N(6)-ethenoadenine (epsilonA), 3,N(4)-ethenocytosine (epsilonC) and N(2),3-ethenoguanine (epsilonG). We studied sequence-specific interaction of the vinyl-chloride metabolite CAA with human p53 gene exons 5-8, using DNA Polymerase Fingerprint Analysis (DPFA), and identified sites of the highest sensitivity. CAA-induced DNA damage was more extensive in p53 regions which revealed secondary structure perturbations, and were localized in regions of mutation hot-spots. These perturbations inhibited DNA synthesis on undamaged template. We also studied the repair kinetics of CAA-induced DNA lesions in E. coli at nucleotide resolution level. A plasmid bearing full length cDNA of human p53 gene was modified in vitro with 360 mM CAA and transformed into E. coli DH5alpha strain, in which the adaptive response system had been induced by MMS treatment before the cells were made competent. Following transformation, plasmids were re-isolated from transformed cultures 35, 40, 50 min and 1-24 h after transformation, and further subjected to LM-PCR, using ANPG, MUG and Fpg glycosylases to identify the sites of DNA damage. In adaptive response-induced E. coli cells the majority of DNA lesions recognized by ANPG glycosylase were removed from plasmid DNA within 35 min, while MUG glycosylase excised base modifications only within 50 min, both in a sequence-dependent manner. In non-adapted cells resolution of plasmid topological forms was perturbed, suggesting inhibition of one or more bacterial topoisomerases by unrepaired epsilon-adducts. We also observed delayed consequences of DNA modification with CAA, manifesting as secondary DNA breaks, which appeared 3 h after transformation of damaged DNA into E. coli, and were repaired after 24 h.
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PMID:Sequence-specific p53 gene damage by chloroacetaldehyde and its repair kinetics in Escherichia coli. 1658 87

The growth arrest and DNA damage-inducible gene 45A (GADD45A) is involved in the DNA repair, maintenance of genomic stability, cell cycle control and apoptosis, and thus plays an important role in cellular response to DNA damage. The GADD45A gene is responsive to a variety of DNA-damaging agents, including ionizing radiation (IR), methyl methanesulfonate (MMS), and ultraviolet (UV) radiation. It is generally thought that induction of the GADD45A gene after IR exposure is principally p53-dependent, requiring binding of the p53 protein to the p53-recognition sequence in the third intron. However, the involvement of factors other than p53 in transcriptional regulation of the GADD45A gene after IR exposure has not been elucidated. In the present study, we show that the 5'-flanking region containing two OCT sites and a CCAAT box, as well as p53 and AP-1 sites in the third intron, are required for the basal transcriptional activity of the reporter gene. In addition, AP-1 recognition element was shown to be involved in the transcriptional enhancement of the GADD45A gene after X-ray irradiation. Electrophoretic mobility shift analysis (EMSA) and Chromatin immunoprecipitation (ChIP) assay revealed that JunD binds to the third intron of the GADD45A gene. These observations suggest that AP-1 complexes containing JunD, in addition to p53, play an important role not only in transcriptional enhancement by IR but also in basal expression of the GADD45A gene via binding to the AP-1 site in the third intron.
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PMID:Both the basal transcriptional activity of the GADD45A gene and its enhancement after ionizing irradiation are mediated by AP-1 element. 1708 16

P53-mediated cellular response has been known to play a crucial role in maintaining genomic stability of mammalian cells against genotoxic stresses. In our previous study, we showed that mild hyperthermia was sufficient to induce apoptosis on p53-dependent pathway in human lymphoid system (Seo et al., 1999), suggesting that mild hyperthermia might be useful for the reducing of genomic instability. However, there have been few reports to show the direct evidence on preventive role of p53 under mild hyperthermia against carcinogenic DNA damage. Here we first show the elimination of MMS-induced micronuclei (MN) as one of biomarkers of carcinogenic risk by p53 activation in human lymphoid cells in response to mild hyperthermia, strongly suggesting a possible protective role of mild hyperthermia in chromosomal stability against genotoxic stresses. Our data might support investigation of the clinical application of mild hyperthermia for the prevention of carcinogenesise in the human lymphoid system.
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PMID:Elimination of methyl methanesulfonate (MMS)-induced micronuclei (MNS) under mild hyperthermia via p53-dependent pathway in human lymphoid cells. 1756 16

As one of a number of p53-regulated genes, Gadd45a (growth arrest and DNA damage inducible gene) has been shown to delay carcinogenesis and decrease mutation frequency. Gadd45a is known to regulate nucleotide excision DNA repair (NER) in response to UV radiation. Here, we report an emerging role for Gadd45a in base excision repair (BER). Gadd45a-null mouse embryo fibroblasts MEF and gadd45a-deficient human colon cancer cells exhibited slow BER after treatment with methyl methanesulfonate (MMS) a pure base-damaging agent. In addition, removal of AP sites by apurinic/apyrimidinic endonuclease 1/redox factor 1 (APE1/Ref1) was significantly delayed in gadd45a-null cells. Moreover, the localization of APE1/Ref1 within the nucleus was observed in gadd45a wild-type cells, whereas APE1 become mainly distributed in the cytoplasm, and there is a reduced interaction with proliferating cell nuclear antigen (PCNA) in Gadd45a-deficient cells. Inasmuch as p53 has been shown to regulate BER in addition to the NER pathway, our data suggest that p53-regulated gene Gadd45a contributes to the BER response by affecting the interaction of cellular APE1/Ref1 with PCNA. Gadd45a might be a key component gene of the p53 pathway involved in protection from carcinogenic base damage and maintenance of genomic stability, although the downstream mechanism including APE1/Ref1 will need further study.
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PMID:Base excision DNA repair defect in Gadd45a-deficient cells. 1759 61

Vascular senescence is closely associated with age-related vascular disorders and is enhanced by angiotensin (Ang) II type 1 receptor stimulation. However, the role of Ang II type 2 receptor activation in vascular senescence is still an enigma. Ang II stimulation significantly increased senescence-associated beta-galactosidase activity and the level of 8-hydroxy-2'-deoxyguanosine, with enhancement of oxidative stress and expression of Ki-ras2A, p53, and p21 in vascular smooth muscle cells (VSMCs) from wild-type (Agtr2(+)) mice, whereas these effects of Ang II were enhanced in VSMCs from Ang II type 2 receptor null (Agtr2(-)) mice. Administration of an Ang II type 1 receptor blocker, valsartan, attenuated these parameters, with less effect in Agtr2(-) VSMCs. Ang II stimulation increased methyl methanesulfonate sensitive 2 (MMS2) expression in Agtr2(+) VSMCs but not in Agtr2(-) VSMCs. MMS2 small-interfering RNA treatment enhanced Ang II-induced senescence-associated beta-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level with no significant changes in oxidative stress markers and the expression of Ki-ras2A, p53, and p21. Moreover, exposure of Agtr2(+) VSMCs to hydrogen peroxide and ultraviolet irradiation induced marked increases in senescence-associated beta-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level, which were further enhanced in Agtr2(-) and MMS2 small-interfering RNA-treated Agtr2(+) VSMCs. Agtr2(+) mice exposed to x-ray irradiation showed increases in senescence-associated beta-galactosidase activity and 8-hydroxy-2'-deoxyguanosine level in the aorta, which were further exaggerated in the aorta of Agtr2(-) mice with a lower MMS2 level. These findings suggest that Ang II type 2 receptor signaling attenuates DNA damage and consequent vascular senescence at least in part through MMS2 transactivation and propose the beneficial effects of Ang II type 2 receptor stimulation with Ang II type 1 receptor blockers in age-related vascular disorders.
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PMID:Angiotensin II type 2 receptor deletion enhances vascular senescence by methyl methanesulfonate sensitive 2 inhibition. 1836 23

When cells traversing G(1) are irradiated with UV light, two parallel damage checkpoint pathways are activated: Chk1-Cdc25A and p53-p21(WAF1/CIP1), both targeting Cdk2, but the latter inducing a long lasting arrest. In similarly treated S phase-progressing cells, however, only the Cdc25A-dependent checkpoint is active. We have recently found that the p21-dependent checkpoint can be activated and induce a prolonged arrest if S phase cells are damaged with a base-modifying agent, such as methyl methanesulfonate (MMS) and cisplatin. But the mechanistic basis for the differential activation of the p21-dependent checkpoint by different DNA damaging agents is not understood. Here we report that treatment of S phase cells with MMS but not a comparable dose of UV light elicits proteasome-mediated degradation of Cdc6, the assembler of pre-replicative complexes, which allows induced p21 to bind Cdk2, thereby extending inactivation of Cdk2 and S phase arrest. Consistently, enforced expression of Cdc6 largely eliminates the prolonged S phase arrest and Cdk2 inactivation induced with MMS, whereas RNA interference-mediated Cdc6 knockdown not only prolongs such arrest and inactivation but also effectively activates the p21-dependent checkpoint in the UV-irradiated S phase cells.
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PMID:Cdc6 determines utilization of p21(WAF1/CIP1)-dependent damage checkpoint in S phase cells. 1845 79

O(6)-Methylguanine produced in DNA induces mutation due to its ambiguous base-pairing properties during DNA replication. To suppress such an outcome, organisms possess a mechanism to eliminate cells carrying O(6)-methylguanine by inducing apoptosis that requires the function of mismatch repair proteins. To identify other factors involved in this apoptotic process, we performed retrovirus-mediated gene-trap mutagenesis and isolated a mutant that acquired resistance to a simple alkylating agent, N-methyl-N-nitrosourea (MNU). However, it was still sensitive to methyl methanesulfonate, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, etoposide and ultraviolet irradiation. Moreover, the mutant exhibited an increased mutant frequency after exposure to MNU. The gene responsible was identified and designated Mapo1 (O(6)-methylguanine-induced apoptosis 1). When the expression of the gene was inhibited by small interfering RNA, MNU-induced apoptosis was significantly suppressed. In the Mapo1-defective mutant cells treated with MNU, the mitochondrial membrane depolarization and caspase-3 activation were severely suppressed, although phosphorylation of p53, CHK1 and histone H2AX was observed. The orthologs of the Mapo1 gene are present in various organisms from nematode to humans. Both mouse and human MAPO1 proteins expressed in cells localize in the cytoplasm. We therefore propose that MAPO1 may play a role in the signal-transduction pathway of apoptosis induced by O(6)-methylguanine-mispaired lesions.
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PMID:A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA. 1913 17

Selenomethionine (SeMet) has been identified as a chemopreventive antioxidant to activate p53-mediated nucleotide excision repair. In this study, we examined whether p53-mediated base excision repair (BER) might be induced by SeMet. When methyl methanesulfonate, a BER-inducing agent, was treated in the cells, DNA damage was rapidly decreased in the presence of SeMet. In addition, our data showed that the removal of apurinic/apyrimidinic sites was significantly enhanced in the presence of SeMet. Furthermore, we observed that the expression of gadd45a, known to involve BER as one of the p53 downstream genes, was increased by SeMet in p53 wild-type RKO cells. Those results supported the proposal that BER activity might be dependent on wild-type p53 under the modulation of gadd45a expression in response to SeMet. We suggested that p53-dependent BER activity as a distinct mechanism of SeMet might play an important role to prevent cancer caused by various oxidative stresses.
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PMID:Enhancement of methyl methanesulfonate-induced base excision repair in the presence of selenomethionine on p53-dependent pathway. 1945 35


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