Vaults and the major vault protein: Novel roles in signal pathway regulation and immunity

The unique and evolutionary highly conserved major vault protein (MVP) is the main component of ubiquitous, large cellular ribonucleoparticles termed vaults. The 100 kDa MVP represents more than 70% of the vault mass which contains two additional proteins, the vault poly (ADP-ribose) polymerase (vPARP) and the telomerase-associated protein 1 (TEP1), as well as several short untranslated RNAs (vRNA). Vaults are almost ubiquitously expressed and, besides chemotherapy resistance, have been implicated in the regulation of several cellular processes including transport mechanisms, signal transmissions and immune responses. Despite a growing amount of data from diverse species and systems, the definition of precise vault functions is still highly complex and challenging. Here we review the current knowledge on MVP and vaults with focus on regulatory functions in intracellular signal transduction and immune defence. Received 27 June 2008; received after revision 25 July 2008; accepted 30 July 2008     

Galectin-3 stabilizes heterogeneous nuclear ribonucleoprotein Q to maintain proliferation of human colon cancer cells

Comparative analysis of proteomes using 5-fluorouracil (5-FU)-resistant human colon cancer cell line revealed that decreased galectin-3 expression was significantly associated with retarded proliferation. However, in the presence of 5-FU proliferation rate of cells with suppressed galectin-3 expression did not differ from that of cells with normal galectin-3 expression, even galectin-3 suppression augmented apoptosis. Mechanism by which galectin-3 regulates cancer cell proliferation has been identified in immunoprecipitates of the anti-galectin-3 antibody. Heterogeneous nuclear ribonucleoprotein Q (hnRNP Q) was identified as a protein interacting with galectin-3. Interestingly, while galectin-3 protein was not affected by the hnRNP Q level, its suppression was accompanied by a decrease in hnRNP Q expression. The present study demonstrates that galectin-3 stabilizes hnRNP Q via complex formation, and reduction in the hnRNP Q level leads to slow proliferation and less susceptibility to 5-FU. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. B.C.Yoo; S-H.Hong; These two authors contributed equally to this work. Received 10 September 2008; received after revision 19 October 2008; accepted 07 November 2008     

恶性肿瘤中IGFBP-rP1的抑癌基因作用机制及其可能的临床实用价值

胰岛素样生长因子结合蛋白相关蛋白1(IGFBP-rP1)是近年来恶性肿瘤的研究热点.本文主要综述IGFBP-rP1在恶性肿瘤中的抑癌基因作用机制及可能的临床实用价值.IGFBP-rP1在恶性肿瘤中的作用广泛涉及细胞的增殖、衰老、凋亡、分化、血管生成等多方面,研究指出IGFBP-rP1可缩短细胞增殖周期并影响非停泊性生长从而抑制增殖,降低致瘤能力;调节BRAF-MEKERK信号通路及pRB、HSP60等相关蛋白的表达从而影响衰老及凋亡;主要通过IGF依赖方式抑制血管生成;而且IGFBP-rP1表达下降跟肿瘤细胞分化程度降低有关.研究显示IGFBP-rP1有一定的临床实用价值,如其表达量跟恶性肿瘤的进展相关,低表达提示某些化疗药物抵抗,可提示预后.而在恶性肿瘤中特异性地上调IGFBP-rP1,可抑制肿瘤增殖及血管生成、诱导细胞衰老凋亡、提高肿瘤分化程度及化疗敏感性,具有治疗意义,但研究者们还在努力探究,争取早日找到一种临床有效的靶向IGFBP-rP1的基因治疗方法.     

Biosynthesis, immunity, regulation, mode of action and engineering of the model lantibiotic nisin

This review discusses the state-of-the-art in molecular research on the most prominent and widely applied lantibiotic, i.e., nisin. The developments in understanding its complex biosynthesis and mode of action are highlighted. Moreover, novel applications arising from engineering either nisin itself, or from the construction of totally novel dehydrated and/or lanthionine-containing peptides with desired bioactivities are described. Several challenges still exist in understanding the immunity system and the unique multiple reactions occurring on a single substrate molecule, carried out by the dehydratase NisB and the cyclization enzyme NisC. The recent elucidation of the 3-D structure of NisC forms the exciting beginning of further 3-D-structure determinations of the other biosynthetic enzymes, transporters and immunity proteins. Advances in achieving in vitro activities of lanthionine-forming enzymes will greatly enhance our understanding of the molecular characteristics of the biosynthesis process, opening up new avenues for developing unique and novel biocatalytic processes. Received 9 April 2007; received after revision 31 August 2007; accepted 28 September 2007     

The cytotoxicity of eosinophil cationic protein/ribonuclease 3 on eukaryotic cell lines takes place through its aggregation on the cell membrane

Human eosinophil cationic protein (ECP)/ ribonuclease 3 (RNase 3) is a protein secreted from the secondary granules of activated eosinophils. Specific properties of ECP contribute to its cytotoxic activities associated with defense mechanisms. In this work the ECP cytotoxic activity on eukaryotic cell lines is analyzed. The ECP effects begin with its binding and aggregation to the cell surface, altering the cell membrane permeability and modifying the cell ionic equilibrium. No internalization of the protein is observed. These signals induce cell-specific morphological and biochemical changes such as chromatin condensation, reversion of membrane asymmetry, reactive oxygen species production and activation of caspase-3-like activity and, eventually, cell death. However, the ribonuclease activity component of ECP is not involved in this process as no RNA degradation is observed. In summary, the cytotoxic effect of ECP is attained through a mechanism different from that of other cytotoxic RNases and may be related with the ECP accumulation associated with the inflammatory processes, in which eosinophils are present. Received 26 October 2007; accepted 23 November 2007     

Myosin V from head to tail

Myosin V (myoV), a processive cargo transporter, has arguably been the most well-studied unconventional myosin of the past decade. Considerable structural information is available for the motor domain, the IQ motifs with bound calmodulin or light chains, and the cargo-binding globular tail, all of which have been crystallized. The repertoire of adapter proteins that link myoV to a particular cargo is becoming better understood, enabling cellular transport processes to be dissected. MyoV is processive, meaning that it takes many steps on actin filaments without dissociating. Its extended lever arm results in long 36-nm steps, making it ideal for single molecule studies of processive movement. In addition, electron microscopy revealed the structure of the inactive, folded conformation of myoV when it is not transporting cargo. This review provides a background on myoV, and highlights recent discoveries that show why myoV will continue to be an active focus of investigation. Received 31 October 2007; received after revision 4 December 2007; accepted 2 January 2008     

The utility F-box for protein destruction

A signature feature of all living organisms is their utilization of proteins to construct molecular machineries that undertake the complex network of cellular activities. The abundance of a protein element is temporally and spatially regulated in two opposing aspects: de novo synthesis to manufacture the required amount of the protein, and destruction of the protein when it is in excess or no longer needed. One major route of protein destruction is coordinated by a set of conserved molecules, the F-box proteins, which promote ubiquitination in the ubiquitin-proteasome pathway. Here we discuss the functions of F-box proteins in several cellular scenarios including cell cycle progression, synapse formation, plant hormone responses, and the circadian clock. We particularly emphasize the mechanisms whereby F-box proteins recruit specific substrates and regulate their abundance in the context of SCF E3 ligases. For some exceptions, we also review how F-box proteins function through non-SCF mechanisms.     

The three-fingered protein domain of the human genome

Extracellular domains of some cellular receptors expressed in the organisms at different levels of development belong to three-fingered protein (TFP) fold. The Homo sapiens genome encodes at least 45 genes containing from one to three TFP domains (TFPDs), namely diverse paralogues of the Ly6 gene, CD59 and the receptors of activins, bone morphogenetic proteins, Mullerian inhibiting substance and transforming growth factor-β. C4.4a and urokinase/plasminogen activatory receptor contain two and three TFPD repeats, respectively. These diverse proteins have a low overall sequence similarity with each other and their hydrophobicity levels vary to a considerable degree. It is suggested that sequence differentiation within the TFPD led to distinct groups of proteins whose attributes were optimized to fit both the physicochemical properties specific to their functional microenvironment and selective targeting of their highly diversified extracellular cofactors. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 7 August 2008; accepted 29 August 2008     

Expansion of amino acid homo-sequences in proteins: Insights into the role of amino acid homo-polymers and of the protein context in aggregation

Expansion of amino acid homo-sequences, such as polyglutamines or polyalanines, in proteins has been directly implicated in various degenerative diseases through a mechanism of protein misfolding and aggregation. However, it is still unclear how the nature of the expansion and the protein context influence the tendency of a protein to aggregate. Here, we have addressed these questions using spinocerebellar ataxia type-3 (ATX3) protein, the best characterised of the polyglutamine proteins, chosen as a model system. Using a transfected mammalian cell line, we demonstrate that ATX3 aggregation is noticeably reduced by deletion or replacement of regions other than the polyglutamine tract. The nature of the amino acid homo-sequences also has a strong influence on aggregation. From our studies, we draw general conclusions on the effect of the protein architecture and of the amino acid homo-sequence on pathology. Received 3 March 2006; received after revision 19 April 2006; accepted 22 May 2006     

Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?

Betaine homocysteine methyltransferase (BHMT), a Zn²⁺-dependent thiolmethyltransferase, contributes to the regulation of homocysteine levels, increases in which are considered a risk factor for cardiovascular diseases. Most plasma homocysteine is generated through the liver methionine cycle, in which BHMT metabolizes approximately 25% of this non-protein amino acid. This process allows recovery of one of the three methylation equivalents used in phosphatidylcholine synthesis through transmethylation, a major homocysteine-producing pathway. Although BHMT has been known for over 40 years, the difficulties encountered in its isolation precluded detailed studies until very recently. Thus, the last 10 years, since the sequence became available, have yielded extensive structural and functional data. Moreover, recent findings offer clues for potential new functions for BHMT. The purpose of this review is to provide an integrated view of the knowledge available on BHMT, and to analyze its putative roles in other processes through interactions uncover to date. Received 26 May 2006; received after revision 3 July 2006; accepted 24 August 2006