Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is a biologic mechanism for eliminating damaged cells from the cell population. Apoptosis is known to be induced by irradiation and can prevent the development of disease states such as carcinogenesis or abnormal tissue formation. On the other hand, if the mechanism is properly controlled, radiotherapy can be used to kill cancer cells more efficiently. Radiation-induced apoptosis is regulated by the balance between cellular anti-apoptotic and (pro-)apoptotic signals. Many regulators of radiation-induced apoptosis have been identified and analyzed. Protein kinase C (PKC) is a family of serine/threonine kinases and one of the regulators in radiation-induced apoptosis. PKC has some subtypes, each of whose functions has been analyzed in radiation-induced signaling cascades. It has been demonstrated that each of PKC subtypes has distinct functions in radiation-induced apoptosis. Moreover, some participants in PKC-related signaling cascades have been identified in radiation-induced apoptosis. Interestingly, PKC-related signaling cascades have been found to be regulated in part by ATM (the gene that is mutated in the human genetic disorder ataxia telangiectasia). ATM is a protein related to cell-cycle checkpoints and cell radiosensitivity, and it also regulates radiation-induced apoptosis. This article reviews recent developments in the understanding of radiation-induced apoptosis, focusing on PKC functions, and the relationship with ATM.
 ...
PMID:Signaling cascades in radiation-induced apoptosis: roles of protein kinase C in the apoptosis regulation. 1700 14

Nbs1, a member of the Mre11-RAD50-Nbs1 complex, is phosphorylated by ATM, the product of the ataxia-telangiectasia mutated gene and a member of the phosphatidylinositol 3-kinase-related family of serine-threonine kinases, in response to DNA double-strand breaks (DSBs) to regulate DNA damage checkpoints. Here we show that BCR/ABL stimulated Nbs1 expression by induction of c-Myc-dependent transactivation and protection from caspase-dependent degradation. BCR/ABL-related fusion tyrosine kinases (FTKs) such as TEL/JAK2, TEL/PDGFbetaR, TEL/ABL, TEL/TRKC, BCR/FGFR1, and NPM/ALK as well as interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) also stimulated Nbs1 expression. Enhanced ATM kinase-dependent phosphorylation of Nbs1 on serine 343 (S343) in response to genotoxic treatment was detected in leukemia cells expressing BCR/ABL and other FTKs in comparison to normal counterparts stimulated with IL-3, GM-CSF, and SCF. Expression of Nbs1-S343A mutant disrupted the intra-S-phase checkpoint, decreased homologous recombinational repair (HRR) activity, down-regulated XIAP expression, and sensitized BCR/ABL-positive cells to cytotoxic drugs. Interestingly, inhibition of Nbs1 phosphorylation by S343A mutant enhanced the antileukemia effect of the combination of imatinib and genotoxic agent.
 ...
PMID:Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells. 1743 Nov 32

Previous work suggested that phosphorylation of DNA-PKcs at several serine/threonine (S/T) residues at positions 2609-2647 promotes DNA-PK-dependent end joining. In an attempt to clarify the role of such phosphorylation, end joining was examined in extracts of DNA-PKcs-deficient M059J cells. Joining of ends requiring gap filling prior to ligation was completely dependent on complementation of these extracts with exogenous DNA-PKcs. DNA-PKcs with either S/T --> A or S/T --> D substitutions at all six sites in the 2609-2647 cluster also supported end joining, but with markedly lower efficiency than wild-type protein. The residual end joining was greater with the S/T --> D-substituted than with the S/T --> A-substituted protein. A specific inhibitor of the kinase activity of DNA-PK, KU57788, completely blocked end joining promoted by wild type as well as both mutant forms of DNA-PK, while inhibition of ATM kinase did not. The fidelity of end joining was not affected by the mutant DNA-PKcs alleles or the inhibitors. Overall, the results support a role for autophosphorylation of the 2609-2647 cluster in promoting end joining and controlling the accessibility of DNA ends, but suggest that DNA-PK-mediated phosphorylation at other sites, on either DNA-PKcs or other proteins, is at least as important as the 2609-2647 cluster in regulating end joining.
 ...
PMID:Phosphorylation in the serine/threonine 2609-2647 cluster promotes but is not essential for DNA-dependent protein kinase-mediated nonhomologous end joining in human whole-cell extracts. 1752 17

Protein phosphatase 5 (PP5) is a unique member of the PPP family of serine/threonine phosphatases based on the presence of tetratricopeptide repeat (TPR) domains within its structure. Since its discovery, PP5 has been implicated in wide ranging cellular processes, including MAPK-mediated growth and differentiation, cell cycle arrest and DNA damage repair via the p53 and ATM/ATR pathways, regulation of ion channels via the membrane receptor for atrial natriuretic peptide, the cellular heat shock response as mediated by heat shock transcription factor, and steroid receptor signaling, especially glucocorticoid receptor (GR). Given this diversity of effects, the recent development of viable PP5-deficient mice was surprising and suggests that PP5 is a modulatory, rather than essential, factor in phosphorylation pathways. Here, we review the signaling involvement of PP5 in light of new findings and relate these activities to the structural features of the protein.
 ...
PMID:Protein phosphatase 5. 1795 Oct 98

To ensure survival in the face of genomic insult, cells have evolved complex mechanisms to respond to DNA damage, termed the DNA damage checkpoint. The serine/threonine kinases ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) activate checkpoint signaling by phosphorylating substrate proteins at SQ/TQ motifs. Although some ATM/ATR substrates (Chk1, p53) have been identified, the lack of a more complete list of substrates limits current understanding of checkpoint pathways. Here, we use immunoaffinity phosphopeptide isolation coupled with mass spectrometry to identify 570 sites phosphorylated in UV-damaged cells, 498 of which are previously undescribed. Semiquantitative analysis yielded 24 known and 192 previously uncharacterized sites differentially phosphorylated upon UV damage, some of which were confirmed by SILAC, Western blotting, and immunoprecipitation/Western blotting. ATR-specific phosphorylation was investigated by using a Seckel syndrome (ATR mutant) cell line. Together, these results provide a rich resource for further deciphering ATM/ATR signaling and the pathways mediating the DNA damage response.
 ...
PMID:Profiling of UV-induced ATM/ATR signaling pathways. 1807 18

The Wild-type p53-induced phosphatase 1, Wip1 (or PPM1D), is unusual in that it is a serine/threonine phosphatase with oncogenic activity. A member of the type 2C phosphatases (PP2Cdelta), Wip1 has been shown to be amplified and overexpressed in multiple human cancer types, including breast and ovarian carcinomas. In rodent primary fibroblast transformation assays, Wip1 cooperates with known oncogenes to induce transformed foci. The recent identification of target proteins that are dephosphorylated by Wip1 has provided mechanistic insights into its oncogenic functions. Wip1 acts as a homeostatic regulator of the DNA damage response by dephosphorylating proteins that are substrates of both ATM and ATR, important DNA damage sensor kinases. Wip1 also suppresses the activity of multiple tumor suppressors, including p53, ATM, p16(INK4a) and ARF. We present evidence that the suppression of p53, p38 MAP kinase, and ATM/ATR signaling pathways by Wip1 are important components of its oncogenicity when it is amplified and overexpressed in human cancers.
 ...
PMID:The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. 1826 45

During the DNA-damage response, adaptor proteins mediate signaling between the PI3K-like sensor kinases, ATM and ATR, and serine/threonine effector kinases. Carballo et al. (2008) now show that the chromosomal protein Hop1 mediates PI3K-like kinase signaling during the repair of DNA double-strand breaks (DSBs) in meiosis.
 ...
PMID:Hop1 and the meiotic DNA-damage response. 1832 59

Forkhead-associated (FHA) domains recognize phosphothreonines, and SQ/TQ cluster domains (SCDs) contain concentrated phosphorylation sites for ATM/ATR-like DNA-damage-response kinases. The Rad53-SCD1 has dual functions in regulating the activation of the Rad53-Dun1 checkpoint kinase cascade but with unknown molecular mechanisms. Here we present structural, biochemical, and genetic evidence that Dun1-FHA possesses an unprecedented diphosphothreonine-binding specificity. The Dun1-FHA has >100-fold increased affinity for diphosphorylated relative to monophosphorylated Rad53-SCD1 due to the presence of two separate phosphothreonine-binding pockets. In vivo, any single threonine of Rad53-SCD1 is sufficient for Rad53 activation and RAD53-dependent survival of DNA damage, but two adjacent phosphothreonines in the Rad53-SCD1 and two phosphothreonine-binding sites in the Dun1-FHA are necessary for Dun1 activation and DUN1-dependent transcriptional responses to DNA damage. The results uncover a phospho-counting mechanism that regulates the specificity of SCD, and provide mechanistic insight into a role of multisite phosphorylation in DNA-damage signaling.
 ...
PMID:Diphosphothreonine-specific interaction between an SQ/TQ cluster and an FHA domain in the Rad53-Dun1 kinase cascade. 1861 39

The kinases ATM and ATR are central to proper function of the DNA damage response. These kinases phosphorylate proteins to coordinate cell cycle progression and DNA damage repair/bypass. We have recently reported a large-scale identification of ATM/ATR substrates phosphorylated in response to UV damage of DNA. Overall 231 sites of phosphorylation were induced by UV damage of DNA or dependent on proper function of ATR. The study expanded the number of phosphorylation sites from protein classes known to be involved in the DNA damage response. Further, many sites were identified from protein types not thought to have a role in damage signaling. This observation suggests that the DNA damage response affects a much wider range of cellular processes than was previously appreciated. This study has also extended the successful use of the PhosphoScan proteomic method from phospho-tyrosine to serine/threonine motifs, providing a general blueprint to use the method to study signaling pathways underlying a wide range of diseases.
 ...
PMID:A wide-ranging cellular response to UV damage of DNA. 1863 54

Upon genotoxic stress, checkpoint machinery in eukaryotic cells induces cell-cycle arrest, thus allowing the cells to repair damaged DNA or stalled replication forks. The checkpoint machinery is mediated by phosphorylation cascades involving protein kinases and their target proteins. Since the genome is under constant threat from DNA damage due to radiation, chemicals and replication errors, checkpoint dysregulation can cause catastrophic DNA damage, resulting in chromosome instability, aneuploidy, and even tumorigenesis. Two parallel pathways that respond to DNA-damage stress have been extensively studied. The first is the ATM pathway, which responds to double-stranded DNA breaks, while the second is the ATR pathway, which primarily responds to agents that interfere with normal DNA replication. The ATM and ATR kinases activate their downstream target proteins by phosphorylating specific serine or threonine residues. Dephosphorylation by protein phosphatase (PP2A) also participates in the regulation of these phosphorylation signals. Of the target proteins, the two effector kinases CHK1 and CHK2 are particularly important because they phosphorylate additional substrates to maintain chromosome stability after various DNA damaging insults. Recent observations indicate that other protein kinases that control centrosome duplication and chromosome segregation during the cell cycle also play essential roles in maintaining genomic stability.
 ...
PMID:Protein kinases that regulate chromosome stability and their downstream targets. 1872 58


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