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951.
Protecting against promiscuity: the regulatory role of insulators 总被引:11,自引:0,他引:11
952.
Cyclin A in cell cycle control and cancer 总被引:16,自引:0,他引:16
953.
The superoxide-generating NADPH oxidase: structural aspects and activation mechanism 总被引:31,自引:0,他引:31
Vignais PV 《Cellular and molecular life sciences : CMLS》2002,59(9):1428-1459
Flavocytochrome b
558
is the catalytic core of the respiratory-burst oxidase, an enzyme complex that catalyzes the NADPH-dependent reduction of
O2 into the superoxide anion O2
- in phagocytic cells. Flavocytochrome b
558
is anchored in the plasma membrane. It is a heterodimer that consists of a large glycoprotein gp91phox (phox for phagocyte oxidase) (β subunit) and a small protein p22phox (α subunit). The other components of the respiratory-burst oxidase are water-soluble
proteins of cytosolic origin, namely p67phox, p47phox, p40phox and Rac. Upon cell stimulation, they assemble with the membrane-bound
flavocytochrome b
558
which becomes activated and generates O2
-. A defect in any of the genes encoding gp91phox, p22phox, p67phox or p47phox results in chronic granulomatous disease, a
genetic disorder characterized by severe and recurrent infections, illustrating the role of O2
- and the derived metabolites H2O2 and HOCl in host defense against invading microorganisms. The electron carriers, FAD and hemes b, and the binding site for NADPH are confined to the gp91phox subunit of flavocytochrome b
558
. The p22phox subunit serves as a docking site for the cytosolic phox proteins. This review provides an overview of current
knowledge on the structural organization of the O2
--generating flavocytochrome b
558
, its kinetics, its mechanism of activation and the regulation of its biosynthesis. Homologues of gp91phox, called Nox and
Duox, are present in a large variety of non-phagocytic cells. They exhibit modest O2
--generating oxidase activity, and some act as proton channels. Their role in various aspects of signal transduction is currently
under investigation and is briefly discussed.
Received 28 May 2002; received after revision 20 June 2002; accepted 24 June 2002 相似文献
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Hoffmann K Dreger CK Olins AL Olins DE Shultz LD Lucke B Karl H Kaps R Müller D Vayá A Aznar J Ware RE Sotelo Cruz N Lindner TH Herrmann H Reis A Sperling K 《Nature genetics》2002,31(4):410-414
Pelger-Hu?t anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape. 相似文献
959.
Walder RY Landau D Meyer P Shalev H Tsolia M Borochowitz Z Boettger MB Beck GE Englehardt RK Carmi R Sheffield VC 《Nature genetics》2002,31(2):171-174
Familial hypomagnesemia with secondary hypocalcemia (OMIM 602014) is an autosomal recessive disease that results in electrolyte abnormalities shortly after birth. Affected individuals show severe hypomagnesemia and hypocalcemia, which lead to seizures and tetany. The disorder has been thought to be caused by a defect in the intestinal absorption of magnesium, rather than by abnormal renal loss of magnesium. Restoring the concentrations of serum magnesium to normal values by high-dose magnesium supplementation can overcome the apparent defect in magnesium absorption and in serum concentrations of calcium. Life-long magnesium supplementation is required to overcome the defect in magnesium handling by these individuals. We previously mapped the gene locus to chromosome 9q in three large inbred kindreds from Israel. Here we report that mutation of TRPM6 causes hypomagnesemia with secondary hypocalcemia and show that individuals carrying mutations in this gene have abnormal renal magnesium excretion. 相似文献
960.
Bulavin DV Demidov ON Saito S Kauraniemi P Phillips C Amundson SA Ambrosino C Sauter G Nebreda AR Anderson CW Kallioniemi A Fornace AJ Appella E 《Nature genetics》2002,31(2):210-215
Expression of oncogenic Ras in primary human cells activates p53, thereby protecting cells from transformation. We show that in Ras-expressing IMR-90 cells, p53 is phosphorylated at Ser33 and Ser46 by the p38 mitogen-activated protein kinase (MAPK). Activity of p38 MAPK is regulated by the p53-inducible phosphatase PPM1D, creating a potential feedback loop. Expression of oncogenic Ras suppresses PPM1D mRNA induction, leaving p53 phosphorylated at Ser33 and Ser46 and in an active state. Retrovirus-mediated overexpression of PPM1D reduced p53 phosphorylation at these sites, abrogated Ras-induced apoptosis and partially rescued cells from cell-cycle arrest. Inactivation of p38 MAPK (the product of Mapk14) in vivo by gene targeting or by PPM1D overexpression expedited tumor formation after injection of mouse embryo fibroblasts (MEFs) expressing E1A+Ras into nude mice. The gene encoding PPM1D (PPM1D, at 17q22/q23) is amplified in human breast-tumor cell lines and in approximately 11% of primary breast tumors, most of which harbor wildtype p53. These findings suggest that inactivation of the p38 MAPK through PPM1D overexpression resulting from PPM1D amplification contributes to the development of human cancers by suppressing p53 activation. 相似文献