Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53

Aurora kinase A (also called STK15 and BTAK) is overexpressed in many human cancers. Ectopic overexpression of aurora kinase A in mammalian cells induces centrosome amplification, chromosome instability and oncogenic transformation, a phenotype characteristic of loss-of-function mutations of p53. Here we show that aurora kinase A phosphorylates p53 at Ser315, leading to its ubiquitination by Mdm2 and proteolysis. p53 is not degraded in the presence of inactive aurora kinase A or ubiquitination-defective Mdm2. Destabilization of p53 by aurora kinase A is abrogated in the presence of mutant Mdm2 that is unable to bind p53 and after repression of Mdm2 by RNA interference. Silencing of aurora kinase A results in less phosphorylation of p53 at Ser315, greater stability of p53 and cell-cycle arrest at G2-M. Cells depleted of aurora kinase A are more sensitive to cisplatin-induced apoptosis, and elevated expression of aurora kinase A abolishes this response. In a sample of bladder tumors with wild-type p53, elevated expression of aurora kinase A was correlated with low p53 concentration. We conclude that aurora kinase A is a key regulatory component of the p53 pathway and that overexpression of aurora kinase A leads to increased degradation of p53, causing downregulation of checkpoint-response pathways and facilitating oncogenic transformation of cells.     

Restriction enzyme-generated siRNA (REGS) vectors and libraries

Small interfering RNA (siRNA) technology facilitates the study of loss of gene function in mammalian cells and animal models, but generating multiple siRNA vectors using oligonucleotides is slow, inefficient and costly. Here we describe a new, enzyme-mediated method for generating numerous functional siRNA constructs from any gene of interest or pool of genes. To test our restriction enzyme-generated siRNA (REGS) system, we silenced a transgene and two endogenous genes and obtained the predicted phenotypes. REGS generated on average 34 unique siRNAs per kilobase of sequence. REGS enabled us to create enzymatically a complex siRNA library (>4 x 10(5) clones) from double-stranded cDNA encompassing known and unknown genes with 96% of the clones containing inserts of the appropriate size.     

Granuloma formation in rat liver after hepatic vein ligation

Summary After occlusion of the hepatic vein draining 1 lobe of the rat liver, macrophage granulomas develop which are reproducible and apparently related to a heat-labile macrophage mobilising factor.     

Novel dominant mutations in Saccharomyces cerevisiae MSH6

Inherited mutations in the mismatch repair (MMR) genes MSH2 and MLH1 are found in most hereditary nonpolyposis colon cancer (HNPCC) patients studied. Eukaryotic MMR uses two partially redundant mispair-recognition complexes, Msh2p-Msh6p and Msh2p-Msh3p (ref.2) Inactivation of MSH2 causes high rates of accumulation of both base-substitution and frameshift mutations. Mutations in MSH6 or MSH3 cause partial defects in MMR, with inactivation of MSH6 resulting in high rates of base-substitution mutations and low rates of frameshift mutations; inactivation of MSH3 results in low rates of frameshift mutations. These different mutator phenotypes provide an explanation for the observation that MSH2 mutations are common in HNPCC families, whereas mutations in MSH3 and MSH6 are rare. We have identified novel missense mutations in Saccharomyces cerevisiae MSH6 that appear to inactivate both Msh2p-Msh6p- and Msh2p-Msh3p-dependent MMR. Our work suggests that such mutations may underlie some cases of inherited cancer susceptibility similar to those caused by MSH2 mutations.     

多被动探测器对多目标定位模型及仿真

对于探测目标间距较小的目标群,提出使用3个被动探测器的探测模型。首先,重点研究了多被动探测器对多目标进行定位的目标关联问题;然后,建立了3个被动探测器的机动模型,提出了3个被动探测器多目标定位的目标关联算法。最后,通过仿真分析了各种因素对目标关联的影响。仿真结果表明提出的3个被动探测器机动模型和目标关联算法是有效的。     

通过探索式教学培养学生的创新能力

以大学本科化学教学实践中的一些具体事例说明,展示了如何把课程中的基础知识与应用实践联系起来构建探索性教学的机会,从而引导学生进行创新思维的活动,培养学生的创新能力.     

王稼祥和平外交战略思想探析

王稼祥是党和国家外交活动的奠基者、开拓者和领导者。在长期的、广泛的外交实践的基础上，他发表了大量的谈话和文章，其中蕴涵着丰富的和平对外战略思想，主要包括坚持不同社会制度国家之间的和平共处、支持世界和平运动，反对帝国主义的战争政策和侵略政策、通过和平谈判的方式解决国际争端、有效地制止战争等方面。这些理论对我国当今外交仍具有巨大的现实意义。     

均匀设计在非离子型微乳液对铝—铬天菁S的增敏作用及增敏条件优选的应用

以吐温／正丁醇／正已烷／水微乳液为介质，进行铝——铬天菁Ｓ的光度法测定，并用微机辅助试验，得到最佳增敏条件。结果表明，与水介质比较，提高了测定灵敏度，某些实验条件更为宽容，样品分析结果令人满意。