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881.
Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome
Gicquel C Rossignol S Cabrol S Houang M Steunou V Barbu V Danton F Thibaud N Le Merrer M Burglen L Bertrand AM Netchine I Le Bouc Y 《Nature genetics》2005,37(9):1003-1007
Silver-Russell syndrome (SRS, OMIM 180860) is a congenital disorder characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features and body asymmetry. SRS is genetically heterogenous with maternal uniparental disomy with respect to chromosome 7 occurring in approximately 10% of affected individuals. Given the crucial role of the 11p15 imprinted region in the control of fetal growth, we hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. We identified an epimutation (demethylation) in the telomeric imprinting center region ICR1 of the 11p15 region in several individuals with clinically typical SRS. This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provide new insight into the pathogenesis of SRS and strongly suggest that the 11p15 imprinted region, in addition to those of 7p11.2-p13 and 7q31-qter, is involved in SRS. 相似文献
882.
The orbital properties of Phoebe, one of Saturn's irregular moons, suggest that it was captured by the ringed planet's gravitational field rather than formed in situ. Phoebe's generally dark surface shows evidence of water ice, but otherwise the surface most closely resembles that of C-type asteroids and small outer Solar System bodies such as Chiron and Pholus that are thought to have originated in the Kuiper belt. A close fly-by of Phoebe by the Cassini-Huygens spacecraft on 11 June 2004 (19 days before the spacecraft entered orbit around Saturn) provided an opportunity to test the hypothesis that this moon did not form in situ during Saturn's formation, but is instead a product of the larger protoplanetary disk or 'solar nebula'. Here we derive the rock-to-ice ratio of Phoebe using its density combined with newly measured oxygen and carbon abundances in the solar photosphere. Phoebe's composition is close to that derived for other solar nebula bodies such as Triton and Pluto, but is very different from that of the regular satellites of Saturn, supporting Phoebe's origin as a captured body from the outer Solar System. 相似文献
883.
884.
Prochownik EV 《Cellular and molecular life sciences : CMLS》2005,62(21):2438-2459
The discovery of oncogenes (c-onc’s) and tumor suppressors (TS’s) has led to the concept that cancer arises from defects in
each of these classes of genes or their products. More recently, it has been appreciated that c-onc and TS proteins often
affect one another’s functions. Within this context, I review the two classical TS’s, p53 and the retinoblastoma protein,
and the consequences of their inactivation. The various forms of genomic instability (GI) that underly the high mutation rates
of transformed cells are then discussed. Particular emphasis is placed upon the concept that GI is not only an integral part
of the transformed state but is a prerequisite. Increased oxidative DNA damage, and/or an inabiliy to repair it, can lead
to GI. The review then discusses recent observations showing that loss of the TS protein peroxiredoxin 1 (prdx1) and increased
expression of the c-onc protein c-Myc, each leads to increased oxidative DNA damage. The critical nature of the c-onc-TS interaction
is underscored by that occurring between prdx1 and c-Myc, with the former protein regulating the production of DNA-damaging
reactive oxygen species by the latter. The intimate association between these proteins and others serves as a paradigm for
the exquisite balancing act that c-onc’s and TS’s must maintain in order to properly control normal DNA replication and cellular
proliferation while simultaneously minimizing the acquisition of potentially neoplastic mutations.
Received 10 May 2005; received after revision 3 July 2005; accepted 19 July 2005 相似文献
885.
Mammalian lactoferrin (Lf) receptors are suggested to have pivotal roles for mediating multiple functions of Lf. In this review, we focus on current knowledge of the structure and function of mammalian Lf receptors, mainly the first cloned Lf receptor that has been shown to be expressed in the infant small intestine at high levels but also in virtually all other tissues. The small intestinal Lf receptor takes up iron from Lf into cells and presumably exerts other physiological functions. Other Lf receptors in various tissues have also been reported to mediate some functions of Lf, such as modulating immune function, inhibiting platelet aggregation and enhancing collagen gel contractile strength. The detailed mechanisms behind the receptor-Lf interactions still need to be elucidated. 相似文献
886.
887.
The most controversial area in protein folding concerns its earliest stages. Questions such as whether there are genuine folding intermediates, and whether the events at the earliest stages are just rearrangements of the denatured state or progress from populated transition states, remain unresolved. The problem is that there is a lack of experimental high-resolution structural information about early folding intermediates and denatured states under conditions that favour folding because competent states spontaneously fold rapidly. Here we have solved directly the solution structure of a true denatured state by nuclear magnetic resonance under conditions that would normally favour folding, and directly studied its equilibrium and kinetic behaviour. We engineered a mutant of Drosophila melanogaster Engrailed homeodomain that folds and unfolds reversibly just by changing ionic strength. At high ionic strength, the mutant L16A is an ultra-fast folding native protein, just like the wild-type protein; however, at physiological ionic strength it is denatured. The denatured state is a well-ordered folding intermediate, poised to fold by docking helices and breaking some non-native interactions. It unfolds relatively progressively with increasingly denaturing conditions, and so superficially resembles a denatured state with properties that vary with conditions. Such ill-defined unfolding is a common feature of early folding intermediate states and accounts for why there are so many controversies about intermediates versus compact denatured states in protein folding. 相似文献
888.
A long-standing hypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells, facilitates the development of aneuploid malignancies. Here we test this idea by transiently blocking cytokinesis in p53-null (p53-/-) mouse mammary epithelial cells (MMECs), enabling the isolation of diploid and tetraploid cultures. The tetraploid cells had an increase in the frequency of whole-chromosome mis-segregation and chromosomal rearrangements. Only the tetraploid cells were transformed in vitro after exposure to a carcinogen. Furthermore, in the absence of carcinogen, only the tetraploid cells gave rise to malignant mammary epithelial cancers when transplanted subcutaneously into nude mice. These tumours all contained numerous non-reciprocal translocations and an 8-30-fold amplification of a chromosomal region containing a cluster of matrix metalloproteinase (MMP) genes. MMP overexpression is linked to mammary tumours in humans and animal models. Thus, tetraploidy enhances the frequency of chromosomal alterations and promotes tumour development in p53-/- MMECs. 相似文献
889.
Global pattern of trends in streamflow and water availability in a changing climate 总被引:16,自引:0,他引:16
Water availability on the continents is important for human health, economic activity, ecosystem function and geophysical processes. Because the saturation vapour pressure of water in air is highly sensitive to temperature, perturbations in the global water cycle are expected to accompany climate warming. Regional patterns of warming-induced changes in surface hydroclimate are complex and less certain than those in temperature, however, with both regional increases and decreases expected in precipitation and runoff. Here we show that an ensemble of 12 climate models exhibits qualitative and statistically significant skill in simulating observed regional patterns of twentieth-century multidecadal changes in streamflow. These models project 10-40% increases in runoff in eastern equatorial Africa, the La Plata basin and high-latitude North America and Eurasia, and 10-30% decreases in runoff in southern Africa, southern Europe, the Middle East and mid-latitude western North America by the year 2050. Such changes in sustainable water availability would have considerable regional-scale consequences for economies as well as ecosystems. 相似文献
890.
Extracellular signalling by the purine nucleotide ATP has long been associated with sensory function. In the periphery, ATP mediates nociception, mechanosensitivity, thermal sensitivity and O2 chemosensitivity. These processes share a common mechanism that involves the release of ATP to excite afferent fibres via activation of ionotropic P2X and/or metabotropic P2Y receptors. Chemosensors located in the brainstem are crucial for the maintenance of physiological levels of blood gases through the regulation of breathing. Here we show that an increase in pCO2 in the arterial blood triggers the immediate release of ATP from three chemosensitive regions located on the ventral surface of the medulla oblongata. Blockade of ATP receptors at these sites diminishes the chemosensory control of breathing, suggesting that ATP release constitutes a key step in central chemosensory transduction. These new data suggest that ATP, a phylogenetically ancient, unique and simple molecule, has been widely used in the evolution of afferent systems to mediate distinct forms of sensory transduction not only in the periphery but also within the central nervous system. 相似文献