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Sadeghi R.N.,Research Center for Gastroenterology and Liver Diseases | Damavand B.,Shahid Beheshti University of Medical Sciences | Vahedi Mohsen,Shahid Beheshti University of Medical Sciences | Mohebbi S.R.,Shahid Beheshti University of Medical Sciences | And 3 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2013

Background: p53 alterations have been implicated in the development of many cancers, such as gastric cancer, but there is no evidence of p53 intron alterations in gastritis lesions. The aim of this study was to investigate the p53 intron alterations in gastritis along with p53 and mismatch repair protein expression and microsatellite status. Materials and Methods: PCR-sequencing was conducted for introns 2-7 on DNA extracted from 97 paired samples of gastritis lesions and normal adjacent tissue. Abnormal accumulation of p53 and mismatch repair proteins was investigated using immunohistochemistry. In addition, microsatellite status was evaluated with reference to five mononucleotide markers. Results: Gastritis cases included 41 males and 56 females in the age range of 15-83 years, 87.6% being H.pylori positive. IVS2+38, IVS3ins16 and IVS7+72 were the most polymorphic sites. Their minor allele frequency values were as follows: 0.38, 0.21 and 0.06, respectively. Samples with GG genotype at IVS2+38 and CT at IVS7+72 had no insertion. Moreover, most of the stable samples (91.9 %) had a G allele at IVS2+38. All of the samples were IHC negative for p53 protein, microsatellite stable and expressed mismatch repair proteins. p53 alterations were prominent in the H. Pylori+ group, but without statistical significance. Conclusions: According to our results, some p53 polymorphisms such as IVS2+38, IVS3ins16 and IVS7+72, because of their correlations together or with microsatellite status may contribute to gastritis development. However, so far effects on p53 expression and function remain unclear. Therefore, a comprehensive survey is needed to delineate their biological significance.

Sadeghi R.N.,University of Tehran | Sadeghi R.N.,Research Center for Gastroenterology and Liver Diseases | Azimzadeh P.,University of Tehran | Vahedi M.,University of Tehran | And 6 more authors.
Digestion | Year: 2010

Background: It has been frequently shown that p53 alterations have an important role in the development of gastric cancers but there is no data on p53 alteration in gastric cancer and its precancerous lesions from Iran although this country experiences one of the highest gastric cancer incidence and mortality rates in the world. The purpose of this study was to do a comprehensive assessment of p53 alterations in the Iranian population of gastritis patients and to evaluate the association between p53 alterations, microsatellite status and clinicopathological aspects. Methods: After DNA extraction, PCR sequencing was done for exons 2-7. Also microsatellite status was evaluated using five microsatellite markers: NR-27, NR-21, NR-24, BAT-25 and BAT-26. Results: The highest rate of alteration was seen in codons 72 (85.6%, SNP) and 248 (30.9%, mutation). Also, we found 2 new mutations in codons 9 and 146. In contrast with previous work, transition at the CpG codons was relatively rare. Nucleotide alterations were more prevalent in the Helicobacter pylori-positive group but not significantly. Neither nuclear staining for p53 protein nor microsatellite instability was seen in gastritis lesions. Conclusion: p53 alterations might contribute to the pathogenesis of gastritis and perhaps gastric cancer in Iran. However, the different spectrum seen here implies other mechanism(s) in gastritis and gastric cancer development in the Iranian population. © 2010 S. Karger AG, Basel.

Tien Y.-C.,National Synchrotron Radiation Research Center | Tien Y.-C.,National Tsing Hua University | Chuankhayan P.,National Synchrotron Radiation Research Center | Huang Y.-C.,National Synchrotron Radiation Research Center | And 7 more authors.
Plant Molecular Biology | Year: 2012

Cytosolic Oryza sativa glyceraldehyde-3-phosphate dehydrogenase (OsGAPDH), the enzyme involved in the ubiquitous glycolysis, catalyzes the oxidative phosphorylation of glyceraldehyde-3-phosphate to 1,3-biphosphoglycerate (BPG) using nicotinamide adenine dinucleotide (NAD) as an electron acceptor. We report crystal structures of OsGAPDH in three conditions of NAD-free, NAD-bound and sulfate-soaked forms to discuss the molecular determinants for coenzyme specificity. The structure of OsGAPDH showed a homotetramer form with each monomer comprising three domains-NAD-binding, catalytic and S-loop domains. NAD binds to each OsGAPDH subunits with some residues forming positively charged grooves that attract sulfate anions, as a simulation of phosphate groups in the product BPG. Phe37 not only forms a bottleneck to improve NAD-binding but also combines with Pro193 and Asp35 as key conserved residues for NAD-specificity in OsGAPDH. The binding of NAD alters the side-chain conformation of Phe37 with a 90° rotation related to the adenine moiety of NAD, concomitant with clamping the active site about 0. 6 Å from the "open" to "closed" form, producing an increased affinity specific for NAD. Phe37 exists only in higher organisms, whereas it is replaced by other residues (Thr or Leu) with smaller side chains in lower organisms, which makes a greater distance between Leu34 and NAD of E. coli GAPDH than that between Phe37 and NAD of OsGAPDH. We demonstrated that Phe37 plays a crucial role in stabilizing NAD binding or intermediating of apo-holo transition, resulting in a greater NAD-dependent catalytic efficiency using site-directed mutagenesis. Phe37 might be introduced by evolution generating a catalytic advantage in cytosolic GAPDH. © 2012 Springer Science+Business Media B.V.

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