Functional and physical communication between oncoproteins and tumor suppressors

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     

Modeling the MHC class I pathway by combining predictions of proteasomal cleavage,TAP transport and MHC class I binding

Epitopes presented by major histocompatibility complex (MHC) class I molecules are selected by a multi-step process. Here we present the first computational prediction of this process based on in vitro experiments characterizing proteasomal cleavage, transport by the transporter associated with antigen processing (TAP) and MHC class I binding. Our novel prediction method for proteasomal cleavages outperforms existing methods when tested on in vitro cleavage data. The analysis of our predictions for a new dataset consisting of 390 endogenously processed MHC class I ligands from cells with known proteasome composition shows that the immunological advantage of switching from constitutive to immunoproteasomes is mainly to suppress the creation of peptides in the cytosol that TAP cannot transport. Furthermore, we show that proteasomes are unlikely to generate MHC class I ligands with a C-terminal lysine residue, suggesting processing of these ligands by a different protease that may be tripeptidyl-peptidase II (TPPII).Received 26 November 2004; received after revision 4 February 2005; accepted 4 March 2005S. Tenzer and B. Peters contributed equally to this work.     

Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway

Enhanced cell migration is one of the underlying mechanisms in cancer invasion and metastasis. Therefore, inhibition of cell migration is considered to be an effective strategy for prevention of cancer metastasis. We found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone), an active component from the rhizome of Rheum palmatum, significantly inhibited epidermal growth factor (EGF)- induced migration in various human cancer cell lines. In the search for the underlying molecular mechanisms, we demonstrated that phosphatidylinositol 3-kinase (PI3K) serves as the molecular target for emodin. In addition, emodin markedly suppressed EGF-induced activation of Cdc42 and Rac1 and the corresponding cytoskeleton changes. Moreover, emodin, but not LY294002, was able to block cell migration in cells transfected with constitutively active (CA)-Cdc42 and CA-Rac1 by interference with the formation of Cdc42/Rac1 and the p21-activated kinase complex. Taken together, data from this study suggest that emodin inhibits human cancer cell migration by suppressing the PI3K-Cdc42/Rac1 signaling pathway.Received 7 February 2005; received after revision 11 March 2005; accepted 18 March 2005     

Lactoferrin

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.     

Is chlamydial heat shock protein 60 a risk factor for oncogenesis?

Heat shock protein 60 (HSP60) plays an important role in the protein folding of prokaryotic and eukaryotic cells. Most of the papers published on chlamydial HSP60 concern its role in immune response during infection. In the last decade, exposure to Chlamydia trachomatis has been consistently associated with the development of cervical and ovarian cancer. Moreover, it has been suggested that chlamydial HSP60 may have an anti-apoptotic effect during persistent infection. We hypothesize that the accumulation of exogenous chlamydial HSP60 in the cytoplasm of actively replicating eukaryotic cells may interfere with the regulation of the apoptotic pathway. The concomitant expression of viral oncoproteins and/or the presence of mutations may lead to the ability to survive apoptotic stimuli, loss of replicative senescence, uncontrolled proliferation and, finally neoplastic transformation.Received 15 August 2004; received after revision 1 October 2004; accepted 7 October 2004     

Bandwidth optimization of a Planar Inverted-F Antenna using binary and real coded genetic algorithms

With the exponential development of mobile communications and the miniaturization of radio frequency transceivers, the need for small and low profile antennas at mobile frequencies is constantly growing. Therefore, new antennas should be developed to provide larger bandwidth and at the same time small dimensions. Although the gain in bandwidth performances of an antenna are directly related to its dimensions in relation to the wavelength, the aim is to keep the overall size of the antenna constant and from ...     

腾冲嗜酸两性菌硫氧化还原酶分子结构中铁原子结合位点的新特征

前期研究表明, 铁原子对于嗜酸两性菌中硫氧化还原酶(SOR)的活性至关重要. 本研究表明, 2,2′-联吡啶、1,2-二羟基苯-3,5-二磺酸钠、8-羟基喹啉等特异性铁离子螯合剂强烈抑制腾冲嗜酸两性菌SOR酶活性, 进一步表明铁原子是SOR酶活必需. 对目前基因组数据库中的SOR基因或者SOR类似基因进行序列比对, 发现了一个潜在的铁原子结合模体(H⁸⁶-X₃- H⁹⁰-X_n-E¹¹⁴-X_n-E¹²⁹). 据此, 本研究采用定点突变技术, 将氨基酸残基H⁸⁶, H⁹⁰和E¹²⁹分别突变为苯丙氨酸或者丙氨酸, 圆二色光谱测定发现突变体(H⁸⁶F, H⁹⁰F和E¹²⁹A)的二级结构没有明显改变, 但是这3个突变体全部丧失了酶活性. 突变体蛋白中铁原子含量测定结果表明, 3个突变体全部或者部分丢失了铁原子, 而之前研究中获得的3个半胱氨酸突变体(完全丧失了酶活)铁原子含量没有变化. 根据本研究并结合前期实验结果可知, SOR分子中模体C³¹-X_n-C¹⁰¹-X₂-C¹⁰⁴是底物硫分子活化区域; 而模体H⁸⁶-X₃-H⁹⁰-X₂₃-E¹¹⁴-X_¹⁴-(E/D)¹²⁹是SOR分子中铁原子的结合区域, 与铁原子结合形成一个非卟啉铁中心, 是SOR的氧化还原中心; 这两个区域均是SOR酶活性的必需部分.     

南京栖霞山铅锌矿山中的现代钙华:一种高度富锌和锰的方解石

金属硫化物矿山开发引发的重金属污染已成为当前急需解决的环境问题. 以南京栖霞山铅锌矿采矿巷道壁上的现代钙华为研究对象, 利用电子探针、扫描电子显微镜和X射线粉末衍射分析等矿物学手段, 分析了钙华中的矿物组成及其重金属元素的赋存形态和分布状况. 结果表明钙华的主要矿物成分为方解石. 尽管地层水的重金属含量较低, 但是钙华中碳酸盐矿物的微量元素含量却较高, 最高含量分别为: Mn 23.65%, Zn 9.60%, Mg 0.76%, Fe 4.44%和Pb 0.66%. 钙华在电子探针背散射电子像中呈现出复杂的韵律壳层构造, 成分分析表明这种韵律壳层构造与重金属的分布有关. 另外, 在钙华中见有螺旋状及团絮状物质可能表明微生物参与了钙华的形成过程, 并与重金属的富集存在关联. 所报道的高度富锌-锰方解石对矿山环境中的重金属污染治理具有可借鉴意义.