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311.
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
312.
All physical implementations of quantum bits (or qubits, the logical elements in a putative quantum computer) must overcome conflicting requirements: the qubits should be manipulable through external signals, while remaining isolated from their environment. Proposals based on quantum optics emphasize optimal isolation, while those following the solid-state route exploit the variability and scalability of nanoscale fabrication techniques. Recently, various designs using superconducting structures have been successfully tested for quantum coherent operation, however, the ultimate goal of reaching coherent evolution over thousands of elementary operations remains a formidable task. Protecting qubits from decoherence by exploiting topological stability is a qualitatively new proposal that holds promise for long decoherence times, but its physical implementation has remained unclear. Here we show how strongly correlated systems developing an isolated twofold degenerate quantum dimer liquid ground state can be used in the construction of topologically stable qubits; we discuss their implementation using Josephson junction arrays. Although the complexity of their architecture challenges the technology base available today, such topological qubits greatly benefit from their built-in fault-tolerance. 相似文献
313.
314.
Genomic imprinting is an epigenetic modification that results in expression from only one of the two parental copies of a gene. Differences in methylation between the two parental chromosomes are often observed at or near imprinted genes. Beckwith-Wiedemann syndrome (BWS), which predisposes to cancer and excessive growth, results from a disruption of imprinted gene expression in chromosome band 11p15.5. One third of individuals with BWS lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene, and it has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS1, 2. Here we show that paternal inheritance of a deletion of KvDMR1 results in the de-repression in cis of six genes, including Cdkn1c, which encodes cyclin-dependent kinase inhibitor 1C. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20-25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings support the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS. 相似文献
315.
Colloids display intriguing transitions between gas, liquid, solid and liquid crystalline phases. Such phase transitions are ubiquitous in nature and have been studied for decades. However, the predictions of phase diagrams are not always realized; systems often become undercooled, supersaturated, or trapped in gel-like states. In many cases the end products strongly depend on the starting position in the phase diagram and discrepancies between predictions and actual observations are due to the intricacies of the dynamics of phase transitions. Colloid science aims to understand the underlying mechanisms of these transitions. Important advances have been made, for example, with new imaging techniques that allow direct observation of individual colloidal particles undergoing phase transitions, revealing some of the secrets of the complex pathways involved. 相似文献
316.
Annexin II light chain regulates sensory neuron-specific sodium channel expression 总被引:16,自引:0,他引:16
The tetrodotoxin-resistant sodium channel Na(V)1.8/SNS is expressed exclusively in sensory neurons and appears to have an important role in pain pathways. Unlike other sodium channels, Na(V)1.8 is poorly expressed in cell lines even in the presence of accessory beta-subunits. Here we identify annexin II light chain (p11) as a regulatory factor that facilitates the expression of Na(V)1.8. p11 binds directly to the amino terminus of Na(V)1.8 and promotes the translocation of Na(V)1.8 to the plasma membrane, producing functional channels. The endogenous Na(V)1.8 current in sensory neurons is inhibited by antisense downregulation of p11 expression. Because direct association with p11 is required for functional expression of Na(V)1.8, disrupting this interaction may be a useful new approach to downregulating Na(V)1.8 and effecting analgesia. 相似文献
317.
DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1 总被引:17,自引:0,他引:17
318.
Boyartchuk VL Broman KW Mosher RE D'Orazio SE Starnbach MN Dietrich WF 《Nature genetics》2001,27(3):259-260
We have used a novel quantitative trait locus model to study the genetics of survival of F2 progeny of susceptible BALB/cByJ and resistant C57BL/6ByJ mice that have been infected with Listeria monocytogenes. This allowed us to map modifiers of L. monocytogenes susceptibility to chromosomes 5 and 13. 相似文献
319.
Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53 总被引:28,自引:0,他引:28
Parant J Chavez-Reyes A Little NA Yan W Reinke V Jochemsen AG Lozano G 《Nature genetics》2001,28(1):92-95
The relationship between the neurosensory photoreceptors and the adjacent retinal pigment epithelium (RPE) controls not only normal retinal function, but also the pathogenesis of hereditary retinal degenerations. The molecular bases for both primary photoreceptor and RPE diseases that cause blindness have been identified. Gene therapy has been used successfully to slow degeneration in rodent models of primary photoreceptor diseases, but efficacy of gene therapy directed at photoreceptors and RPE in a large-animal model of human disease has not been reported. Here we study one of the most clinically severe retinal degenerations, Leber congenital amaurosis (LCA). LCA causes near total blindness in infancy and can result from mutations in RPE65 (LCA, type II; MIM 180069 and 204100). A naturally occurring animal model, the RPE65-/- dog, suffers from early and severe visual impairment similar to that seen in human LCA. We used a recombinant adeno-associated virus (AAV) carrying wild-type RPE65 (AAV-RPE65) to test the efficacy of gene therapy in this model. Our results indicate that visual function was restored in this large animal model of childhood blindness. 相似文献
320.
Culture in low levels of oxygen enhances in vitro proliferation potential of satellite cells from old skeletal muscles 总被引:4,自引:0,他引:4
Chakravarthy MV Spangenburg EE Booth FW 《Cellular and molecular life sciences : CMLS》2001,58(8):1150-1158
The proliferation ability of satellite cells (considered the 'stem cells' of mature myofibers) declines with increasing age
when cultured under standard cell culture conditions of 21% oxygen. However, actual oxygen levels in the intact myofiber in
vivo are an order of magnitude lower. No studies to date have addressed the issue of whether culturing satellite cells from
old muscles under more 'physiologic' conditions would enhance their proliferation and/or differentiation ability. Therefore,
we analyzed satellite cells derived from 31-month-old rats in standard cultures with 21% O2 and in lowered (∼3%) O2. Under the lowered O2 conditions, we noted a remarkable increase in the percentage of large-sized colonies, activation of cell cycle progression
factors, phosphorylation of Akt, and downregulation of the cell cycle inhibitor p27Kip1. These data suggest that lower O2 levels provide a milieu that stimulates proliferation by allowing continued cell cycle progression, to result ultimately
in the enhanced in vitro replicative life span of the old satellite cells. Such a method therefore provides an improved means
for the ex vivo generation of progenitor satellite cell populations for potential therapeutic stem cell transplantation.
Received 20 April 2001; received after revision 28 May 2001; accepted 31 May 2001 相似文献