Article

ATM signaling and 53BP1.

The Wistar Institute, USA.
Radiotherapy and Oncology (Impact Factor: 4.86). 09/2005; 76(2):119-22. DOI: 10.1016/j.radonc.2005.06.026
Source: PubMed

ABSTRACT The ATM (mutated in Ataxia-Telangiectasia) protein kinase is an important player in signaling the presence of DNA double strand breaks (DSBs) in higher eukaryotes. Recent studies suggest that ATM monitors the presence of DNA DSBs indirectly, through DNA DSB-induced changes in chromatin structure. One of the proteins that sense these chromatin structure changes is 53BP1, a DNA damage checkpoint protein conserved in all eukaryotes and the putative ortholog of the S. cerevisiae RAD9 protein. We review here the mechanisms by which ATM is activated in response to DNA DSBs, as well as key ATM substrates that control cell cycle progression, apoptosis and DNA repair.

0 Followers
 · 
138 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Model accuracy plays a key role in the performance of advanced, model predictive control algorithms. Model fidelity is usually affected by routine operating condition changes, which necessitate reidentification. From several theoretical and practical considerations, it is recommended that such re-identification be performed under closed-loop conditions. The direct approach for closed-loop identification, owing to its simplicity, is better suited for MPC. In order to yield unbiased and consistent parameter estimates, however, this approach requires the noise model to be sufficiently parameterized. Towards this objective, high order ARX models are the most suitable candidates from the viewpoint of ease of parameter estimation. For multivariable systems, however, the identification of high order ARX models would require longer experiments to be performed. This being undesirable from a practical viewpoint, there is a need for a parsimonious parameterization that would retain the benefits of high order ARX models. In this work, we propose to use generalized orthonormal basis filters (GOBFs) to achieve this parsimonous parameterization. Further, we propose an approach to obtain reduced order models by emphasizing important frequencies so as to suitably shape the bias. We also show that the choice of the GOBF parameterization has another important merit, viz. their ability to perform well even with minimal perturbation data or short experiment times. The efficacy of the proposed approach is demonstrated via simulations on the benchmark Shell Control Problem and a laboratory quadruple tank setup.
    Journal of Process Control 08/2011; 21(7):1056-1071. DOI:10.1016/j.jprocont.2011.05.007 · 2.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Methylglyoxal (MGO), a glucose derived dicarbonyl intermediate, is a major precursor of advanced glycation end products (AGEs) which have been linked to the development of diabetic cataract. Protocatechualdehyde (PCA), a phenolic acid compound, is found in the roots of Salvia miltiorrhiza. This study was to investigate the effect of PCA against MGO-induced cytotoxicity in human lens epithelial cells (SRA01/04 cells) and the possible involved molecular mechanism. The results showed that PCA alleviated MGO-induced mitochondrial dysfunction and apoptosis in SRA01/04 cells. Furthermore, PCA was capable of inhibiting MGO-mediated AGEs formation and blocking receptor of AGEs expression in SRA01/04 cells. It is concluded that PCA could be useful in attenuation of MGO-induced cell damage and the possible mechanism is involved in modulating AGEs-receptor of AGEs axis in human lens epithelial cells, which suggests that PCA has a potential protective effect on diabetic cataract.
    European Journal of Pharmacology 06/2014; 738. DOI:10.1016/j.ejphar.2014.04.045 · 2.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cytochrome P450 2A13 (CYP2A13) is an extrahepatic enzyme that mainly expresses in human respiratory system, and it is reported to mediate the metabolic activation of aflatoxin B1. Due to the structural similarity, AFG1 is predicted to be metabolized by CYP2A13. However, the role of CYP2A13 in metabolic activation of AFG1 is unclear. In present study, human bronchial epithelial cells that stably express CYP2A13 (B-2A13) were used to conduct the effects of AFG1 on cytotoxicity, apoptosis, DNA damages, and their response protein expression. Low concentrations of AFG1 induced significant cytotoxicity and apoptosis, which was consistent with the increased expressions of pro-apoptotic proteins, such as C-PARP and C-caspase-3. In addition, AFG1 increased 8-OHdG and γH2AX in the nuclies and induced S phase arrest and DNA damage in B-2A13 cells, and the proteins related to DNA damage responses, such as ATM, ATR, Chk2, p53, BRCA1, and γH2AX, were activated. All the above effects were inhibited by nicotine (a substrate of CYP2A13) or 8-MOP (an inhibitor of CYP enzymes), confirming that CYP2A13 mediated the AFG1-induced cytotoxicity and DNA damages. Collectively, our findings first demonstrate that CYP2A13 might be an efficient enzyme in metabolic activation of AFG1 and helps provide a new insight into adverse effects of AFG1 in human respiratory system.
    Archives of Toxicology 08/2013; DOI:10.1007/s00204-013-1108-3 · 5.08 Impact Factor