Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12

FKBP12, a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitously expressed and interacts with proteins in several intracellular signal transduction systems(1). Although FKBP12 interacts with the cytoplasmic domains of type I receptors of the transforming growth factor-beta (TGF-beta) superfamily in vitro, the function of FKBP12 in TGF-beta superfamily signalling is controversial(2-6). FKBP12 also physically interacts stoichiometrically with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine dine receptor (RyR1)(7,8). In contrast, the cardiac ryanodine receptor, RyR2, appears to bind selectively the FKBP12 homologue, FKBP12.6 (refs 9, 10). To define the functions of FKBP12 in vivo, we generated mutant mice deficient in FKBP12 using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal skeletal muscle but have severe dilated cardiomyopathy and ventricular septal defects that mimic a human congenital heart disorder, noncompaction of left ventricular myocardium(11,12). About 9% of the mutants exhibit exencephaly secondary to a defect in neural tube closure. Physiological studies demonstrate that FKBP12 is dispensable for TGF-beta-mediated signalling, but modulates the calcium release activity of both skeletal and cardiac ryanodine receptors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62697/1/391489a0.pd

Increased expression of survivin in gastric cancer patients and in first degree relatives

Survivin was recently described as an apoptosis inhibitor. Its pathogenic role in gastric cancer is largely unknown. Expression of survivin in gastric cancer and non-cancer first-degree relatives, and its association with apoptosis and cyclo-oxygenase-2 expression was investigated. Fifty gastric cancer, 30 non-cancer first-degree relatives, 20 normal controls and five gastric cancer cell lines were studied. Survivin and cyclo-oxygenase-2 were evaluated by reverse transcriptase-polymerase chain reaction, immunohistochemistry and Western blot. Survivin expression was absent from normal gastric mucosa. All five cancer cell lines and 34 out of 50 (68%) human gastric cancer tissues expressed survivin mRNA. Survivin expression was less frequent (22%; P<0.001) in adjacent non-tumour gastric tissues. Immunohistochemistry and Western blot obtained similar findings. Gastric cancers with survivin expression displayed significantly reduced apoptosis (P=0.02), and associated with cyclo-oxygenase-2 overexpression at both mRNA (P=0.001) and protein levels (P=0.041). Moreover, survivin mRNA was detected in the gastric mucosa of eight (27%) non-cancer relatives. Expression in non-cancer patients showed positive correlation with H. pylori infection (P=0.004). This demonstrates the frequent expression of survivin in gastric cancer and in first-degree relatives. Co-expression of survivin and cyclo-oxygenase-2 may suggest multiple pathways contributing to the inhibition of apoptosis in gastric cancer. © 2002 Cancer Research UK.link_to_subscribed_fulltex

Molecular structure, vibrational spectral investigation and the confirmation analysis of 4-Methylesculetin molecule

WOS: 000333614200003In this work, FT-IR, FT-Raman, and FT-NMR spectra of 4-Methylesculetin molecule are presented for the first time. FT-IR, FT-Raman, and FT-NMR spectra of 4MEC have been recorded and analyzed. The FT-IR and FT-Raman spectra of this molecule are recorded at 4000-400 cm(-1) and 50-3500 cm(-1), respectively. The infrared vibrational frequencies, absolute intensities, potential energy profile, HOMO-LUMO plot and NBO analysis of the molecule have been also predicted using Becke's three-parameter hybrid B3LYP method in the density functional theory DFT method. Calculated and experimental data are in good agreement.Ahi Evran University Research FundAhi Evran University [FEN.4003.12.013]Y. Erdogdu would like to thank Ahi Evran University Research Fund for its financial support. Project Numbers: FEN.4003.12.013. Computing resources used in this work were provided by the National Center for High Performance Computing of Turkey (UYBHM)