Understanding microtubule dynamics for improved cancer therapy

Microtubules (MTs), key components of the cytoskeleton, are dynamic polymers of tubulin that form a well-organized network of polarized tube filaments. MT dynamics are highly regulated both spacially and temporally by several MT-related proteins, themselves regulated by several kinases and phosphatases via signaling cascades, and also by coordinated interactions with actin cytoskeleton and adhesion sites. Regulation of MT dynamics is crucial for mitosis, cell migration, cell signaling and trafficking. MT-targeted drugs (MTDs), which constitute a major anticancer drug family with antimitotic and antiangiogenic properties, inhibit tumor progression mainly by altering MT dynamics in both cancer and endothelial cells. Identification of proteins regulating the MT network will lead to a better understanding of tumor progression regulators and will be helpful in improving cancer therapy. Received 22 July 2005; received after revision 8 September 2005; accepted 12 September 2005     

Microtubule dynamics

Microtubules are fibrous elements in the cytoplasm of eukaryotic cells, where they perform a wide variety of functions. Microtubules are major organizers of the cell interior and are vitally involved in motility events such as chromosome migration during cell division. To fulfill their physiological function, microtubule arrays have to undergo dramatic changes in their spatial arrangement, and this depends to a large extent on the complex and special dynamic properties of the individual polymers. In this review we first describe the intrinsic dynamic properties of microtubules assembled in vitro from purified tubulin and examine the relationships between these properties and microtubule functions. Subsequent sections concern microtubule dynamics in vivo, their similarity and differences with microtubule dynamics in vitro, and the nature of the cellular regulators which act on microtubule assemblies in physiological conditions. Received 2 May 2001; received after revision 10 July 2001; accepted 10 July 2001     

Regulation and interactions in the activation of cell-associated plasminogen

The main components in plasminogen activation include plasminogen, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR), and plasminogen activator inhibitors-1 and –2 (PAI-1, PAI-2). These components are subject to extensive regulation and interactions with for example, pericellular adhesion molecules. Although uPA and tPA are quite similar in structure and have common inhibitors and physiological substrates, their physiological roles are distinct. Traditionally, the role of tPA has been in fibrinolysis and that of uPA in cell migration, especially in cancer cells. Recently several targets for tPA/plasmin have been found in neuronal tissues. The functional role of the PAIs is no longer simply to inhibit overexpressed plasminogen activators, and PAI-2 has an unidentified role in the regulation of cell death.Received 2 June 2004; received after revision 30 June 2004; accepted 20 July 2004     

Structural organization and cellular localization of tuftelin-interacting protein 11 (TFIP11)

Tuftelin-interacting protein (TFIP11) was first identified in a yeast two-hybrid screening as a protein interacting with tuftelin. The ubiquitous expression of TFIP11 suggested that it might have other functions in non-dental tissues. TFIP11 contains a G-patch, a protein domain believed to be involved in RNA binding. Using a green fluorescence protein tag, TFIP11 was found to locate in a novel subnuclear structure that we refer to as the TFIP body. An in vivo splicing assay demonstrated that TFIP11 is a novel splicing factor. TFIP11 diffuses from the TFIP body following RNase A treatment, suggesting that the retention of TFIP11 is RNA dependent. RNA polymerase II inhibitor (-amanitin and actinomycin D) treatment causes enlargement in size and decrease in number of TFIP bodies, suggesting that TFIP bodies perform a storage function rather than an active splicing function. The TFIP body may therefore represent a new subnuclear storage compartment for splicing components.Received 8 December 2004; received after revision 27 January 2005; accepted 8 March 2004The nucleotide sequence for the cDNA to mouse TFIP11 (previously known as TIP39 and TIP39kDa) has been submitted to Gen- Bank^TM/ EBI Data Bank with accession numbers AF290474 and NM_018783. The accession number for the human TFIP11 homologueis NM_012143.     

Unit responses and interactions at superior colliculus first stage of input reception

Zusammenfassung Durch Stimulation der visuellen corticalen Zone 17 und 18 des Pulvinarnukleus und des tractus opticus wurden Reiz-Potentiale von SC-Neuronen abgeleitet. Die präkonditionierte Stimulation des visuellen corticalen Zone 18 ergab ein konstantes Reiz-Muster.     

国内外运载火箭POGO抑制技术研究进展

本文描述了美国、前苏联、欧洲、日本和中国等国内外运载火箭跷振（POGO）抑制技术研究的发展历程及进展,并总结出国内外火箭POGO抑制技术的特点,以及在小POGO和气蚀动力学等方面带来的启示.美国的POGO抑制技术研究经历了大力神2——土星V——航天飞机——具体问题具体分析等4个阶段的发展历程,中国的POGO抑制技术研究也类似经历了331工程——载人航天工程——新一代火箭——40 Hz问题等4个阶段.由此可知,POGO振动抑制呈现出＂事前理论预示难度大、事后危害后果严重、解决过程漫长曲折＂的特点,必须在重大航天工程实施前开展研究.     

Functions and malfunctions of the tau proteins

The tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play major regulatory roles in the organization and integrity of the cytoskeleton network. Neurofibrillary changes of abnormally hyperphosphorylated tau are a key lesion in Alzheimer's disease and a number of other tauopathies. However, despite an ever-increasing body of data on the changes which tau undergoes in disease, its role regarding the fundamental disease process is still unclear. Moreover, conceptions of tau functions continue to evolve, which complicates an understanding of its role in the disease process. This review attempts to summarize data on the role of tau proteins in the context of both normal cellular function and dysfunction. Furthermore, we try to develop a mechanistic framework for the involvement of tau during the disease process. The review closes with a look towards various approaches to elucidate the functions and malfunctions of tau. Received 21 June 2002; received after revision 24 July 2002; accepted 29 July 2002 RID="*" ID="*"Corresponding author.     

Mechanisms of glial-guided neuronal migration in vitro and in vivo

Summary Our laboratory has developed an in vitro model system in which glial-guided neuronal migration can be observed in real time. Cerebellar granule neurons migrate on astroglial fibers by apposing their cell soma against the glial arm, forming a specialized migration junction, and extending a motile leading process in the direction of migration. In vitro assays indicate that the neuronal antigen astrotactin functions as a neuron-glia ligand, and is likely to play a role in the movement of neurons along glial fibers. In heterotypic recombinations of neurons and glia from mouse cerebellum and rat hippocampus, neurons migrate on heterotypic glial processes with a cytology, speed and mode of movement identical to that of neuronal migration on homotypic glial fibers, suggesting that glial fibers provide a permissive pathway for neuronal migration in developing brain. In vivo analyses of developing cerebellum demonstrate a close coordination of afferent axon ingrowth relative to target cell migration. These studies indicate that climbing fibers contact immature Purkinje neurons during the migration and settling of Purkinje cells, implicating a role for afferents in the termination of migration.     

Tropomodulins and tropomodulin/tropomyosin interactions

The tropomodulins are a family of proteins that cap the slow-growing (pointed) end of actin filaments and require tropomyosin for optimal function. Tropomodulin is an elongated molecule with a molecular mass of about 40 kDa. The C-terminal half of tropomodulin contains one compact cooperatively melting domain, whereas the N-terminal half has no cooperatively melting structure. The N-terminal half of tropomodulin contains two tropomysin-binding sites and a tropomyosin-dependent actin-binding site, the tropomyosin-independent actin-binding site being located at the C terminus. One tropomodulin molecule binds two tropomyosin molecules, and thus one molecule of tropomodulin is necessary and sufficient for capping at the pointed end. Tropomyosin/tropomodulin interactions are isoform specific. Differences in tropomyosin affinity for the two binding sites in tropomodulin may regulate its correct positioning at the pointed end as well as effectiveness of capping the actin filament. Received 30 July 2007; received after revision 2 October 2007; accepted 10 October 2007     

ER-to-Golgi transport and cytoskeletal interactions in animal cells

The endoplasmic reticulum (ER)-Golgi system has been studied using biochemical, genetic, electron and light microscopic techniques. We now understand many aspects of trafficking from the ER to the Golgi apparatus, including some of the signals and mechanisms for selective retention and retrieval of ER resident proteins and export of cargo proteins. Proteins that leave the ER emerge in export complexes or ER exit sites and accumulate in pleiomorphic transport carriers referred to sometimes as VTCs or intermediate compartments. These structures then transit from the ER to the Golgi apparatus along microtubules using the dynein/dynactin motor and fuse with the cis cisterna of the Golgi apparatus. Many proteins (including vSNAREs, ERGIC53/p58 and the KDEL receptor) must cycle back to the ER from pre-Golgi intermediates or the Golgi. We will discuss both the currently favored model that this cycling occurs via 50-nm COPI-coated vesicles and in vivo evidence that suggests retrograde trafficking may occur via tubular structures.     

Cellular regulation and molecular interactions of the ferritins

Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA (mRNA) structures, signaling pathways and protein catalysts. Ferritin, a protein nanocage around an iron/oxy mineral, centralizes the control. Complementary DNA (antioxidant responsive element/Maf recognition element) and mRNA (iron responsive element) responses regulate ferritin synthesis rates. Multiple iron-protein interactions control iron and oxygen substrate movement through the protein cage, from dynamic gated pores to catalytic sites related to di-iron oxygenase cofactor sites. Maxi-ferritins concentrate iron for the bio-synthesis of iron/heme proteins, trapping oxygen; bacterial mini-ferritins, DNA protection during starvation proteins, reverse the substrate roles, destroying oxidants, trapping iron and protecting DNA. Ferritin is nature’s unique and conserved approach to controlled, safe use of iron and oxygen, with protein synthesis in animals adjusted by dual, genetic DNA and mRNA sequences that selectively respond to iron or oxidant signals and link ferritin to proteins of iron, oxygen and antioxidant metabolism. Received 25 June 2005; received after revision 17 October 2005; accepted 25 November 2005     

Teratogenic interactions between cadmium and radiation in mice

Summary Mouse embryos were exposed to various doses of cadmium and/or X-rays on day 8 of gestation. The combined treatment exerted an antagonistic effect regarding the teratogenic action of the two agents.     

Chemical evidence for interactions between vitamins E and C

Summary Experimental proof is provided for interactions between radicals of vitamin E/vitamin C as generated by air-oxidized lipids (liquid fraction of subcutaneous chicken fat). Using ESR spectroscopy, hydrogen atom exchange is shown to take place between vitamin C and the radical of vitamin E. Sequential consumption of these two vitamins in oxidized lipid, first vitamin C then vitamin E, is demonstrated by means of differential pulse polarography. These results elucidate the in vitro radical scavenging functions attributed to vitamin E and vitamin C as well as their synergism in lipid antioxidation.The authors very much thank Dr A. Dieffenbacher and P. Ducret for the preparation of the chicken fat fraction.     

Protein level in the haemolymph of the waspPolistes gallicus L. at the beginning of imaginal life and during overwintering. Action of the strepsiterian parasiteXenos vesparum rossi

Summary During the imaginal life of malePolistes wasps, the protein concentration in the haemolymph remained constant. In females, there were 2 groups; one in which this concentration was also stable and another in which it increased. No difference was detected between the haemolymphatic protein level of stylopized males and normal ones. All parasitized females exhibited low haemolymph protein levels similar to those of the low level group.