The Polycomb group protein EZH2 directly controls DNA methylation

The establishment and maintenance of epigenetic gene silencing is fundamental to cell determination and function. The essential epigenetic systems involved in heritable repression of gene activity are the Polycomb group (PcG) proteins and the DNA methylation systems. Here we show that the corresponding silencing pathways are mechanistically linked. We find that the PcG protein EZH2 (Enhancer of Zeste homolog 2) interacts-within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)-with DNA methyltransferases (DNMTs) and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicate that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Furthermore, we show by bisulphite genomic sequencing that EZH2 is required for DNA methylation of EZH2-target promoters. Our results suggest that EZH2 serves as a recruitment platform for DNA methyltransferases, thus highlighting a previously unrecognized direct connection between two key epigenetic repression systems.     

The mahogany protein is a receptor involved in suppression of obesity

Genetic studies have shown that mutations within the mahogany locus suppress the pleiotropic phenotypes, including obesity, of the agouti-lethal-yellow mutant. Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppressor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately involved in the regulation of body weight and feeding. We present new genetic studies that indicate that the mahogany locus does not suppress the obese phenotype of the melanocortin-4-receptor null allele or those of the monogenic obese models (Lep(db), tub and Cpe(fat)). However, mahogany can suppress diet-induced obesity, the mechanism of which is likely to have implications for therapeutic intervention in common human obesity. The amino-acid sequence of the mahogany protein suggests that it is a large, single-transmembrane-domain receptor-like molecule, with a short cytoplasmic tail containing a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan receptors such as fibroblast growth factor and transforming growth factor-beta, and the other suggests that mahogany itself is a signalling receptor.     

Phosphatidylglycerol is involved in protein translocation across Escherichia coli inner membranes

Newly synthesized proteins to be exported out of the cytoplasm of bacterial cells have to pass across the inner membrane. In Gram-negative bacteria ATP, a membrane potential, the products of the sec genes and leader peptidases (enzymes which cleave the N-terminal signal peptides of the precursor proteins) are required. The mechanism of translocation, however, remains elusive. Important additional roles for membrane lipids have been repeatedly suggested both on theoretical grounds and on the basis of experiments with model systems but no direct evidence had been obtained. We demonstrate here, using mutants of Escherichia coli defective in the synthesis of the major anionic membrane phospholipids, that phosphatidylglycerol is involved in the translocation of newly synthesized outer-membrane proteins across the inner membrane.     

The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis

Fas is a cell-surface receptor molecule that relays apoptotic (cell death) signals into cells. When Fas is activated by binding of its ligand, the proteolytic protein caspase-8 is recruited to a signalling complex known as DISC by binding to a Fas-associated adapter protein. A large new protein, FLASH, has now been identified by cloning of its complementary DNA. This protein contains a motif with oligomerizing activity whose sequence is similar to that of the Caenorhabditis elegans protein CED-4, and another domain (DRD domain) that interacts with a death-effector domain in caspase-8 or in the adapter protein. Stimulated Fas binds FLASH, so FLASH is probably a component of the DISC signalling complex. Transient expression of FLASH activates caspase-8, whereas overexpression of a truncated form of FLASH containing only one of its DRD or CED-4-like domains does not allow activation of caspase-8 and Fas-mediated apoptosis to occur. Overexpression of full-length FLASH blocks the anti-apoptotic effect of the adenovirus protein E1B19K. FLASH is therefore necessary for the activation of caspase-8 in Fas-mediated apoptosis.     

Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis

Many mammalian viruses have acquired genes from their hosts during their evolution. The rationale for these acquisitions is usually quite clear: the captured genes are subverted to provide a selective advantage to the virus. Here we describe the opposite situation, where a viral gene has been sequestered to serve an important function in the physiology of a mammalian host. This gene, encoding a protein that we have called syncytin, is the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W. We find that the major sites of syncytin expression are placental syncytiotrophoblasts, multinucleated cells that originate from fetal trophoblasts. We show that expression of recombinant syncytin in a wide variety of cell types induces the formation of giant syncytia, and that fusion of a human trophoblastic cell line expressing endogenous syncytin can be inhibited by an anti-syncytin antiserum. Our data indicate that syncytin may mediate placental cytotrophoblast fusion in vivo, and thus may be important in human placental morphogenesis.     

Deg1 is involved in the degradation of the PsbO oxygen-evolving protein of photosystem II in Arabidopsis

Deg1, a thylakoid lumen-localized protease, retains both chaperone and protease activities. The in vivo function of Deg1 has been shown to be involved not only in PSII assembly but also in the degradation of PSII reaction center protein D1. Here we used the transgenic plants with reduced Deg1 to examine whether the lumen-localized proteins are also the substrates of Deg1 in vivo. Our results showed that the transgenic plants accumulated degradation products of the PsbO protein while the levels of full-length PsbO were not affected. The PsbO degradation products could be efficiently degraded by the recombinant Deg1. These results suggest that Deg1 is involved in the degradation of the PsbO degradation fragments, but not in the initial cleavage event itself.     

以整合素为靶点治疗乳腺癌的研究进展

乳腺癌是严重影响妇女身心健康甚至危及生命的最常见肿瘤之一,发病率占各种恶性肿瘤的7%～10%.乳腺癌通常发生于乳房腺上皮组织,绝经期前后的妇女发病率较高.男性乳腺癌罕见,仅占乳腺癌患者的1%～2%.整合素是细胞表面受体的主要家族,介导细胞和细胞外基质的黏附,介导细胞间的相互作用.整合素在生物体内广泛表达,在许多生命活动中发挥着关键的作用.整合素与癌症进程密切相关,在转移性肿瘤中某些整合素高表达,并与蛋白水解酶相互作用,导致基底膜降解.整合素通过重塑细胞外基质在肿瘤的迁移和侵袭中起着重要作用.综述了以整合素为靶点治疗乳腺癌的新进展.     

An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2

Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH, phenylalanine 4-monooxygenase, EC 1.14.16.1). PKU is a common inborn error of amino-acid metabolism in caucasian populations and approximately 1 in 50 individuals are carriers of a PKU allele. To define the molecular basis of PKU, we characterized twelve restriction fragment-length polymorphism (RFLP) haplotypes of the PAH locus in the northern European population and observed that 90% of the PKU alleles in this population are confined to four common RFLP haplotypes. We have recently reported a splicing mutation in the PAH gene that is associated with RFLP haplotype 3 which is present at about 40% of mutant alleles. We now report the molecular lesion associated with the RFLP haplotype 2 mutant allele. This defect is caused by a C-to-T transition in exon 12 resulting in an amino-acid substitution (Arg to Trp) at residue 408 of PAH. Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is also in linkage disequilibrium with RFLP haplotype 2 alleles that make up about 20% of mutant PAH genes.     

A vertebrate actin-related protein is a component of a multisubunit complex involved in microtubule-based vesicle motility.

Actin is a cytoskeletal protein which is highly conserved across eukaryotic phyla. Actin filaments, in association with a family of myosin motor proteins, are required for cellular motile processes as diverse as vesicle transport, cell locomotion and cytokinesis. Many organisms have several closely related actin isoforms. In addition to conventional actins, yeasts contain actin-related proteins that are essential for viability. We show here that vertebrates also contain an actin-related protein (actin-RPV). Actin-RPV is a major component of the dynactin complex, an activator of dynein-driven vesicle movement, indicating that unlike conventional actins which work in conjunction with myosin motors, actin-RPV may be involved in cytoplasmic movements via a microtubule-based system.     

血清PSA指标与经直肠超声造影对前列腺癌的诊断

目的:探讨血清前列腺特异性抗原(PSA)指标,游离前列腺特异性抗原(f-PSA)、总前列腺特异性抗原(T-PSA),前列腺特异性抗原密度(PSAD)与经直肠前列腺超声造影对前列腺癌(Prostate Cancer,PCa)的诊断价值.方法:获取59例血清PSA升高的患者的f PSA及T-PSA、前列腺体积的三个径(L、W、H),所有病例均经直肠超声造影检查,并在超声引导下进行前列腺穿刺.结果:前列腺癌组患者的发病年龄要比良性前列腺增生(Benign prostate hyperplasia,BPH)组大,PSAD比BPH组高.前列腺癌组的f/T-PSA比良性前列腺增生组低.前列腺癌组患者的显影时间、达峰时间、加速时间较良性前列腺增生组患者短,绝对增强强度较良性前列腺增生组高.前列腺癌组患者的强度减半时间比良性前列腺增生组患者短.结论:前列腺癌组的前列腺造影结果表现为"快进快出".血清f/T-PSA、PSAD及经直肠超声造影技术对前列腺良恶性病变的鉴别诊断具有一定的临床价值.     

Stromal fibroblasts in cancer initiation and progression

It is widely accepted that the development of carcinoma--the most common form of human cancer--is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications.