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

Although many lines of evidence have suggested that angiotensin II (Ang II) plays an important role in development of cardiac hypertrophy, the mechanism by which Ang II increases protein synthesis in cardiac myocytes remains unclear. It has been reported that the phosphorylation of S6 protein in 40 S ribosome is correlated to the efficiency of protein synthesis. In the present study, we have examined whether Ang II activates p70 S6 kinase (p70S6K), which has been reported to phosphorylate S6 protein. Ang II activated p70S6K through AT1 receptor. An immunosuppressant agent, rapamycin, inhibited Ang II-induced p70S6K activation but not the activation of MAP kinases or the induction of c-fos gene expression. Rapamycin also abolished Ang II-induced increase in protein synthesis. These results suggest that Ang II induces cardiac hypertrophy by activating p70S6K.
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PMID:Activation of p70 S6 protein kinase is necessary for angiotensin II-induced hypertrophy in neonatal rat cardiac myocytes. 860 1

Rapamycin, a potent immunosuppressive agent, binds two proteins: the FK506-binding protein (FKBP12) and the FKBP-rapamycin-associated protein (FRAP). A crystal structure of the ternary complex of human FKBP12, rapamycin, and the FKBP12-rapamycin-binding (FRB) domain of human FRAP at a resolution of 2.7 angstroms revealed the two proteins bound together as a result of the ability of rapamycin to occupy two different hydrophobic binding pockets simultaneously. The structure shows extensive interactions between rapamycin and both proteins, but fewer interactions between the proteins. The structure of the FRB domain of FRAP clarifies both rapamycin-independent and -dependent effects observed for mutants of FRAP and its homologs in the family of proteins related to the ataxia-telangiectasia mutant gene product, and it illustrates how a small cell-permeable molecule can mediate protein dimerization.
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PMID:Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. 866 94

Certain growth regulatory kinases contain a common domain related to the phospho-inositol 3 (PI-3) kinase catalytic site. These include the ATM gene product, DNA-PKcs, and the target of rapamycin (TOR in yeast; and FRAP in mammalian cells). Rapamycin inhibits growth factor signalling and induces G1 arrest in many cell types. Some growth regulatory PI-3 kinases appear functionally linked to p53 and we have explored potential links between cellular effects induced by rapamycin and p53. In p53 null cells rapamycin inhibited cell cycling but did not induce G1 arrest. In cells which showed selective G1 arrest in response to rapamycin, rapamycin had no effect on basal levels of p53 protein. Similarly p21(WAF1) protein was not induced by rapamycin. The kinetics of the cellular p53/p21(WAF1) response to ionising radiation was unaffected by rapamycin; and the ability of growth factor to protect against p53-mediated apoptosis in response to DNA damage was also unaffected by rapamycin. The ATM gene is mutated in the cancer susceptibility syndrome ataxia telangiectasia (AT) but such mutant cells showed a similar sensitivity to rapamycin compared to their normal counterparts. RKO cell lines of common genetic background, but with different levels of functional p53 protein, also responded similarly to rapamycin. Thus, although rapamycin and p53 are each able to induce G1 arrest, they appear to act through independent growth regulatory pathways.
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PMID:Rapamycin and p53 act on different pathways to induce G1 arrest in mammalian cells. 934 96

Several pyrrolo-quinoline gamma-lactones were found as novel inhibitors for two members of the PI3-kinase related kinase (PIKK) family, Ataxia-Telangiectasia-mutated (ATM) protein and the mammalian Target of Rapamycin (mTOR). Preliminary structure-activity relationship studies indicated that an electrophilic exocyclic double bond conjugated to the carbonyl group of the gamma-lactone ring was crucial for the PIKK inhibitory potency. One of the best ATM inhibitors in this series, DK8G557, showed IC(50) values of 0.6 and 7.0 microM for ATM and mTOR, respectively. This compound exhibited potent and selective growth inhibition activities in the NCI 60 human tumor cell line screen with a GI(50) MG-MID value of 2.69 microM. The best mTOR inhibitor in this series, HP9912, exhibited IC(50) values of 0.5 and 6.5 microM for mTOR and ATM, respectively. These compounds suggest novel leads for the discovery of potent small molecule inhibitors of PIKKs as potential anticancer drugs, with therapeutic activities as either single, or as sensitizing agents to conventional radio-, or chemo-therapeutic strategies.
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PMID:Novel pyrrolo-quinoline derivatives as potent inhibitors for PI3-kinase related kinases. 1173 18

Rapamycin induces chromosome malsegregation in mammalian cell lines and yeast. Previous studies indicate that the function impaired in ataxia-telangiectasia (A-T) patients is necessary for both the growth inhibition and the chromosome malsegregation induced by rapamycin, and that treating the non-tumorigenic Chinese hamster cell line CHEF/18 with rapamycin results in supernumerary centrosomes and multipolar spindles. In this paper we report that lymphoblastoid cell lines established from A-T patients as well as hamster A-T-like cells are more resistant to rapamycin than the respective normal cell lines. Two cell lines derived from Nijmegen Breakage Syndrome (NBS) patients, who have clinical symptoms similar to those of A-T but a different molecular defect, were not resistant to rapamycin. Both A-T lymphoblastoid cells and A-T-like fibroblasts had giant centrosomes formed by more than two areas of gamma-tubulin-reacting material. Such giant centrosomes were also observed in CHEF/18 cells after prolonged treatment with rapamycin. Formation of giant centrosomes, possibly due to the coalescence of supernumerary centrosomes, was associated with increased aneuploidy in treated cells. Expression analysis of cell-cycle regulatory genes in rapamycin-treated human lymphoblastoid cells indicated that rapamycin decreased the expression of the tumor suppressor gene GADD45. The levels of RB, p21 and p53 mRNA were also decreased, although to a lesser extent. As rapamycin is often used as an immunosuppressant in pediatric transplant patients, these data indicate that caution should be taken, especially when the drug is given for prolonged periods of time.
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PMID:Altered centrosomes in ataxia-telangiectasia cells and rapamycin-treated Chinese hamster cells. 1592 Jul 52

The Target Of Rapamycin (TOR) kinase belongs to the highly conserved eukaryotic family of phosphatidylinositol-3-kinase-related kinases (PIKKs). TOR proteins are found at the core of two distinct evolutionarily conserved complexes, TORC1 and TORC2. Disruption of TORC1 or TORC2 results in characteristically dissimilar phenotypes. TORC1 is a major cell growth regulator, while the cellular roles of TORC2 are not well understood. In the fission yeast Schizosaccharomyces pombe, Tor1 is a component of the TORC2 complex, which is particularly required during starvation and various stress conditions. Our genome-wide gene expression analysis of Deltator1 mutants indicates an extensive similarity with chromatin structure mutants. Consistently, TORC2 regulates several chromatin-mediated functions, including gene silencing, telomere length maintenance, and tolerance to DNA damage. These novel cellular roles of TORC2 are rapamycin insensitive. Cells lacking Tor1 are highly sensitive to the DNA-damaging drugs hydroxyurea (HU) and methyl methanesulfonate, similar to mutants of the checkpoint kinase Rad3 (ATR). Unlike Rad3, Tor1 is not required for the cell cycle arrest in the presence of damaged DNA. Instead, Tor1 becomes essential for dephosphorylation and reactivation of the cyclin-dependent kinase Cdc2, thus allowing reentry into mitosis following recovery from DNA replication arrest. Taken together, our data highlight critical roles for TORC2 in chromatin metabolism and in promoting mitotic entry, most notably after recovery from DNA-damaging conditions. These data place TOR proteins in line with other PIKK members, such as ATM and ATR, as guardians of genome stability.
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PMID:TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions. 1954 37

Cellular senescence is currently viewed as a response to DNA damage. In this report, we showed that non-damaging agents such as sodium butyrate-induced p21 and ectopic expression of either p21 or p16 cause cellular senescence without detectable DNA breaks. Nevertheless, senescent cells displayed components of DNA damage response (DDR) such as gammaH2AX foci and uniform nuclear staining for p-ATM. Importantly, there was no accumulation of 53BP1 in gammaH2AX foci of senescent cells. Consistently, comet assay failed to detect DNA damage. Rapamycin, an inhibitor of mTO R, which was shown to suppress cellular senescence, decreased gammaH2AX foci formation. Thus, cellular senescence leads to activation of atypical DDR without detectable DNA damage. Pseudo-DDR may be a marker of general over-activation of senescent cells.
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PMID:Pseudo-DNA damage response in senescent cells. 1995 35

Protein acetylation is mediated by histone acetyltransferases (HATs) and deacetylases (HDACs), which influence chromatin dynamics, protein turnover and the DNA damage response. ATM and ATR mediate DNA damage checkpoints by sensing double-strand breaks and single-strand-DNA-RFA nucleofilaments, respectively. However, it is unclear how acetylation modulates the DNA damage response. Here we show that HDAC inhibition/ablation specifically counteracts yeast Mec1 (orthologue of human ATR) activation, double-strand-break processing and single-strand-DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CtIP) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3, and one HAT, Gcn5, have key roles in these processes. We also find that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of hda1 and rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor, also causes Sae2 degradation. We propose that Rpd3, Hda1 and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand-break processing with autophagy.
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PMID:HDACs link the DNA damage response, processing of double-strand breaks and autophagy. 2136 22

A balanced diet reduces the risk of life-threatening diseases such as diabetes and cancer. A reduced supply of energy at the cellular level leads to an increased concentration of AMP, which, in turn, results in LKB1-mediated activation of the AMPK kinase. The activation of the p53 tumor suppressor protein by metabolic stress has been shown to be mediated by AMPK. Increased intracellular AMP can be mimicked by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). We showed that AICAR activated the p53 pathway in LKB1-deficient cells. This activation was strongly attenuated by two inhibitors of the ATM kinase (caffeine and Ku-55933), which is dysfunctional in ataxia-telanagiectasia patients. In cells with ATM expression silenced by shRNA, AICAR-induced p53 phosphorylation at Ser(15) and Ser(37) was attenuated. Furthermore, p53 activation by AICAR was blocked by rapamycin, a specific inhibitor of the mTOR kinase, which is a crucial regulator of cell growth. Rapamycin did not block p53 activation by resveratrol, which, in contrast to AICAR, induced the DNA damage response, senescence-like growth inhibition, a high level of post-translational modification of p53, and weak upregulation of MDM2 (the negative regulator of p53). Thus, ATM and mTOR participate in the activation of p53 in response to a compound mimicking metabolic stress.
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PMID:The activation of the p53 pathway by the AMP mimetic AICAR is reduced by inhibitors of the ATM or mTOR kinases. 2194 51

Epstein-Barr virus (EBV), a human herpesvirus, is linked to both epithelial and lymphoid malignancies. Induction of EBV reactivation is a potential therapeutic strategy for EBV-associated tumors. In this study, we assessed the effects of rapamycin on EBV reactivation in gastric carcinoma cells. We found that rapamycin upregulated expression of EBV lytic proteins and increased the viral proliferation triggered by the EBV lytic inducer sodium butyrate. Reverse transcription-qPCR, luciferase activity assays, chromatin immunoprecipitation and western blotting were employed to explore the mechanism by which rapamycin promotes EBV reactivation. Our results showed that rapamycin treatment resulted in increased mRNA levels of EBV immediate-early genes. Rapamycin also enhanced the transcriptional activities of the EBV immediate-early lytic promoters Zp and Rp by strengthening Sp1 binding. Repression of the cellular ataxia telangiectasia-mutated/p53 pathway by siRNA-mediated knockdown of the ataxia telangiectasia-mutated gene significantly abrogated virus reactivation by rapamycin/sodium butyrate treatment, indicating that the ataxia telangiectasia-mutated/p53 pathway is involved in rapamycin-promoted EBV reactivation. Taken together, these findings demonstrate that rapamycin might have the potential to enhance the effectiveness of oncolytic viral therapies developed for EBV-associated malignancies.
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PMID:Rapamycin enhances lytic replication of Epstein-Barr virus in gastric carcinoma cells by increasing the transcriptional activities of immediate-early lytic promoters. 2916 30


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