Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Solar UVA, but not UVC, reaches the earth's surface and therefore is an important etiological factor for the induction of human skin cancer. ATM kinase is an important regulator of cell survival and cell cycle checkpoints. Here, we observe that UVA, unlike UVC, triggers ATM kinase activity, and the activation may occur through reactive oxygen species produced after irradiation of cells with UVA. We also show that ATM activation is involved in the apoptotic response to UVA but not UVC. Furthermore, we provide evidence that ATM-dependent p53 and c-Jun N-terminal kinase (JNK) pathways are linked to UVA-induced apoptosis. On the other hand, UVC-induced apoptosis occurs through ATR-dependent p53 phosphorylation as well as the JNK pathway. Therefore, these results suggest that ATM, like p53, is involved in the UVA-induced apoptosis to suppress carcinogenesis.
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PMID:Requirement of ATM in UVA-induced signaling and apoptosis. 1172 37

A general overview of the activation mechanisms of programmed cell death or apoptosis following an irradiation is given in this review. First, are summarized the main induction pathways of radiation-induced apoptosis by which extracellular (tumor necrosis factor (TNF), Fas ligand, TNF-related apoptosis-inducing ligand (TRAIL)) and intracellular (mitochondria and caspases) signals are integrated. A second part is then devoted to the importance of p53 and of its regulators (ATR, ATM, DNA-PKcs) in the process of radiation-induced apoptosis. Thereafter, signal transduction pathways and more specially the role of some protein kinases (MEKK, SAPK/JNK, p38-MAPK) is treated. At last, a chapter concerns the clinical interest of radiation-induced apoptosis and the implication of apoptosis in the treatment of certain diseases.
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PMID:[Mechanisms of radio-induced apoptosis]. 1218 18

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

Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatin-based chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologic-based mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.
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PMID:Cisplatin: mode of cytotoxic action and molecular basis of resistance. 1457 37

The nucleolus is the site of ribosomal gene transcription, processing of rRNA transcripts and maturation of preribosomal particles. Recent studies have shown that nucleoli are also involved in processes as diverse as aging, proliferation control, stress response and mitotic regulation. The proliferation-dependent nucleolar antigen pKi-67 is a sensitive marker of both proliferative activity and nucleolar integrity. We show that staining for the nucleolar-associated antigen pKi-67 is lost from nucleoli during growth arrest following UV irradiation. Surprisingly, before cells enter growth arrest, Ki-67 staining translocates from nucleolar to nucleoplasmic sites within 4-6 h of irradiation. Ki-67 redistribution is accompanied by segregation of nucleolar components. The timing of p53 response correlates well with pKi-67 translocation, growth arrest and restoration of proliferation. However, nucleolar segregation and pKi-67 translocation occur in the absence of functional p53 and other components of damage response pathways (DNA-PK, CSA, CSB, XPA, XPC, ATM ATR, p38(MAPK) and MEK1). Neither gamma-irradiation nor H(2)O(2) treatment causes pKi-67 translocation or loss of nucleolar integrity. In marked contrast, treatment of cells with UV-mimetic 4-NQO does induce nucleolar disruption and relocalisation of pKi-67, suggesting that bulky adduct formation in rDNA rather than strand breaks is sufficient to cause nucleolar segregation. Our data reveal a previously unrecognized cellular response to genotoxic stress and may reveal novel pathways leading to growth arrest.
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PMID:A p53-independent pathway regulates nucleolar segregation and antigen translocation in response to DNA damage induced by UV irradiation. 1472 May 17

Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114) is one of a new class of anticancer agents that are semisynthetic derivatives of the mushroom toxin illudin S. Preclinical studies and clinical trials have demonstrated that irofulven is effective against several tumor types. Mechanisms of action studies indicate that irofulven induces DNA damage, MAPK activation, and apoptosis. In this study we found that in ovarian cancer cells, CHK2 kinase is activated by irofulven while CHK1 kinase is not activated even when treated at higher concentrations of the drug. By using GM00847 human fibroblast expressing tetracycline-controlled, FLAG-tagged kinase-dead ATR (ATR.kd), it was demonstrated that ATR kinase does not play a major role in irofulven-induced CHK2 activation. Results from human fibroblasts proficient or deficient in ATM function (GM00637 and GM05849) indicated that CHK2 activation by irofulven is mediated by the upstream ATM kinase. Phosphorylation of ATM on Ser(1981), which is critical for kinase activation, was observed in ovarian cancer cell lines treated with irofulven. RNA interference results confirmed that CHK2 activation was inhibited after introducing siRNA for ATM. Finally, experiments done with human colon cancer cell line HCT116 and its isogenic CHK2 knockout derivative; and experiments done by expressing kinase-dead CHK2 in an ovarian cancer cell line demonstrated that CHK2 activation contributes to irofulven-induced S phase arrest. In addition, it was shown that NBS1, SMC1, and p53 were phosphorylated in an ATM-dependent manner, and p53 phosphorylation on serine 20 is dependent on CHK2 after irofulven treatment. In summary, we found that the anticancer agent, irofulven, activates the ATM-CHK2 DNA damage-signaling pathway, and CHK2 activation contributes to S phase cell cycle arrest induced by irofulven.
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PMID:ATM-dependent CHK2 activation induced by anticancer agent, irofulven. 1526 3

The reactive metabolites of benzo[a]pyrene (B[a]P) and cyclopenta[c,d]pyrene (CPP) induced an accumulation/phosphorylation of p53 in Hepa1c1c7 cells, whereas inhibition of p53 reduced the apoptosis. Judged by the inhibiting effect of wortmannin, phosphatidyl-inositol-3 (PI-3) kinases such as DNA-dependent protein kinase (DNA-PK), ATM (ataxia-telangiectasia mutated), and/or ATR (ATM related kinase), appeared to be involved in the DNA damage recognition and the B[a]P-/CPP-induced accumulation of p53. B[a]P and CPP also induced phosphorylation of jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK). While inhibition of JNK had no effects on the B[a]P-/CPP-induced apoptosis, inhibition of p38 MAPK activity reduced this effect. Interestingly, survival signals such as phosphorylation of Akt and Bad seemed to be induced by the B[a]P-/CPP-compounds. Furthermore, also extracellular signal-regulated kinase (ERK)1/2 was activated and seemed to function as a survival signal in B[a]P-/CPP-induced apoptosis.
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PMID:Role of cell signalling involved in induction of apoptosis by benzo[a]pyrene and cyclopenta[c,d]pyrene in Hepa1c1c7 cells. 1544 20

In the present study, we employed a well established JB6 mouse epithelial cell model to define the molecular mechanism of efficacy of a naturally occurring flavonoid silibinin against ultraviolet B (UVB)-induced skin tumorigenesis. UVB exposure of cells caused a moderate phosphorylation of ERK1/2 and Akt and a stronger phosphorylation of p53 at Ser(15), which was enhanced markedly by silibinin pretreatment. Kinase activity of ERK1/2 for Elk-1 and Akt for glycogen synthase kinase-3beta was also potently enhanced by silibinin pretreatment. Furthermore, silibinin increased the UVB-induced level of cleaved caspase 3 as well as apoptotic cells. Based on these observations, next we investigated the role of upstream kinases, ATM/ATR and DNA-PK, which act as sensors for UVB-induced DNA damage and transduce signals leading to DNA repair or apoptosis. Whereas UVB strongly activated ATM as observed by Ser(1981) phosphorylation, it was not affected by silibinin pretreatment. However, pretreatment of cells with the DNA-protein kinase (PK) inhibitor LY294002 strongly reversed silibinin-enhanced Akt-Ser(473) and p53-Ser(15) as well as ERK1/2 phosphorylation together with a dose-dependent decrease in cleaved caspase 3 and apoptosis (p < 0.05). In addition, silibinin pretreatment strongly enhanced H2A.X-Ser(139) phosphorylation and DNA-PK-associated kinase activity as well as the physical interaction of p53 with DNA-PK; pretreatment of cells with LY294002 but not caffeine abolished the silibinin-caused increase in both DNA-PK activation and p53-Ser(15) phosphorylations. Together, these findings suggest that silibinin preferentially activates the DNA-PK-p53 pathway for apoptosis in response to UVB-induced DNA damage, and that this could be a predominant mechanism of silibinin efficacy against UVB-induced skin cancer.
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PMID:Silibinin up-regulates DNA-protein kinase-dependent p53 activation to enhance UVB-induced apoptosis in mouse epithelial JB6 cells. 1579 56

Most anticancer drugs presently used clinically target genomic DNA. The selectivity of these anticancer drugs for tumor tissues is probably due to tumor-specific defects suppressing cell cycle checkpoints and DNA repair, and enhancing apoptotic response in the tumor. We will review the molecular interactions within the ATM-Chk2 pathway implicating the DNA damage sensor kinases (ATM, ATR and DNA-PK), the adaptor BRCT proteins (Nbs1, Brca1, 53BP1, MDC1) and the effector kinases (Chk2, Chk1, Plk3, JNK, p38). The molecular interaction map convention (MIM) will be used for presenting this molecular network (http://discover.nci.nih.gov/mim/). A characteristic of the ATM-Chk2 pathway is its redundancy. First, ATM and Chk2 phosphorylate common substrates including p53, E2F1, BRCA1, and Chk2 itself, which suggests that Chk2 (also known as CHECK2, Cds1 in fission yeast, and Dmchk2 or Dmnk or Loki in the fruit fly) acts as a relay for ATM and/or as a salvage pathway when ATM is inactivated. Secondly, redundancy is apparent for the substrates, which can be phosphorylated/activated at similar residues by Chk2, Chk1, and the polo kinases (Plk's). Functionally, Chk2 can activate both apoptosis (via p53, E2F1 and PML) and cell cycle checkpoint (via Cdc25A and Cdc25C, p53, and BRCA1). We will review the short list of published Chk2 inhibitors. We will also propose a novel paradigm for screening interfacial inhibitors of Chk2. Chk2 inhibitors might be used to enhance the tumor selectivity of DNA targeted agents in p53-deficient tumors, and for the treatment of tumors whose growth depends on enhanced Chk2 activity.
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PMID:Targeting chk2 kinase: molecular interaction maps and therapeutic rationale. 1610 42

Camptothecin (CPT) is a potent inhibitor of DNA topoisomerase I with a wide spectrum of anti-tumor activity. Relatively little information is available regarding the relation of known topoisomerase-mediated DNA damage with other intracellular pathways. To gain an insight into the intracellular molecular mechanisms of Topoisomerase I inhibitor camptothecin-mediated DNA damage leading to cell death, we used a high-density cDNA microarray to assess sensitive early gene expression profiles in SGC7901 (gastric cancer), Hela (cervical adenocarcinoma), K562 (chronic myelogenous leukemia) and HL60 (promyelocytic leukemia) tumor cells stimulated with camptothecin for 1 h at the concentrations of GI50 (50 % growth inhibition after 24 h of treatment). Analysis of the differentially expressed genes obtained 29 response genes common to all four cell lines. Moreover, these cell lines also shared the direction of regulation. Most of these common response genes were functionally related to cell proliferation or apoptosis, and some of them were involved in ATM (ataxia-telangiectasia mutated) and ATR (ATM-and Rad3 related) checkpoint pathways, JNK (c-Jun N-terminal kinase) pathway, the survival phosphatidylinositol (PI) 3 kinase-Akt-dependent pathway, mitochondrial cell death pathway, endoplasmic reticulum (ER)-related cell death pathway, and to ubiquitin/proteasome dependent protein degradation pathway. The data provides evidence for a linkage between topoisomerase-mediated DNA damage and intracellular signaling events, which may facilitate our understanding of the camptothecin mediated molecular mechanisms of action.
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PMID:Analysis of common gene expression patterns in four human tumor cell lines exposed to camptothecin using cDNA microarray: identification of topoisomerase-mediated DNA damage response pathways. 1636 68


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