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Tropomyosin assembly intermediates in the control of MF-system turnover
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
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2008 (English)In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 87, no 11, 905-920 p.Article in journal (Refereed) Published
Abstract [en]

Tropomyosin is a coiled-coil α-helical protein, which self-associates in a head-to-tail fashion along polymers of actin to produce thin filaments. Mammalian non-muscle cells express a large number of tropomyosin isoforms, which are differentially regulated during embryogenesis and associated with specialized actin microfilament ensembles in cells. The function of tropomyosin in specifying form and localization of these subcellular structures, and the precise mechanism(s) by which they carry out their functions, is unclear. This paper reports that, while the major fraction of non-muscle cell tropomyosin resides in actin thin filaments of the cytomatrix, the soluble part of the cytoplasm contains tropomyosins in the form of actin-free multimers, which are isoform specific and of high molecular weight (MWapp 180,000–250,000). Stimulation of motile cells with growth factors induces a rapid, actin polymerization-dependent outgrowth of lamellipodia and filopodia. Concomitantly, the levels of tropomyosin isoform-specific multimers decrease, suggesting their involvement in actin thin filament formation. Malignant tumor cells have drastically altered levels and composition of tropomyosin isoform-specific multimers as well as tropomyosin in the cytomatrix.

Place, publisher, year, edition, pages
2008. Vol. 87, no 11, 905-920 p.
Keyword [en]
Actin, Tropomyosin, Tropomyosin multimers, Lamellipodia, Filopodia, Tumorigenesis
Identifiers
URN: urn:nbn:se:su:diva-25021DOI: 10.1016/j.ejcb.2008.06.006ISI: 000260600800004OAI: oai:DiVA.org:su-25021DiVA: diva2:198733
Note
Part of urn:nbn:se:su:diva-7633Available from: 2008-05-12 Created: 2008-05-02 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Elements in regulation of the microfilament system
Open this publication in new window or tab >>Elements in regulation of the microfilament system
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with cell motility. The process of rapid actin polymerization in the lamellipodium of a migrating cell is responsible for its protrusion. Studies have been made on some of the elements behind this event and special interest has been focused on the protein tropomyosin. Muscle tropomyosin and its function in regulating muscle contraction, have been studied for decades, but there are also multiple tropomyosin isoforms in non-muscle cells, whose detailed function has not been revealed. Previous work at this department has shown an involvement of tropomyosin in the assembly of actin in vitro in the presence of gelsolin, and initial studies located tropomyosin to the lamellipodium of stimulated human fibroblasts. However, the general view is that tropomyosin is depleted from the advancing cell edge, observations noted in support of the current model of Arp2/3 dependent formation of actin filaments in lamellipodia. We have demonstrated the presence of tropomyosins in lamellae of migrating cells using different antibodies against non-muscle tropomyosin in indirect immunofluorescence. Also, the distribution of tagged non-muscle tropomyosin isoforms was analyzed in transfected cells. We conclude that tropomyosin is present in lamellipodia, all the way to their advancing edges. The presence of tropomyosin in the leading edge urges for tropomyosin to be taken into account when modelling cell motility. Furthermore, the nature of cytosolic tropomyosin was investigated by gel filtration chromatography and the conclusion was that in fibroblasts, approximately 10% of the tropomyosin is present in the cytosol, while the remaining 90% is associated with actin microfilaments in the cytomatrix. Interestingly, the soluble tropomyosin was found to exist mostly in a multimeric form of high molecular weight. Surprisingly, skeletal muscle tropomyosin and recombinant TM1 expressed in Escherichia coli forms multimers, a phenomenon not observed previously.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi, 2008. 46 p.
Keyword
cell motility, microfilament system, actin, tropomyosin
National Category
Biochemistry and Molecular Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-7633 (URN)978-91-7155-667-7 (ISBN)
Public defence
2008-06-02, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 8 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2008-05-12 Created: 2008-05-02 Last updated: 2012-01-12Bibliographically approved
2. Tropomyosin in Normal and Malignant Cells and the Action of Picropodophyllin on the Microfilament and Microtubule Systems
Open this publication in new window or tab >>Tropomyosin in Normal and Malignant Cells and the Action of Picropodophyllin on the Microfilament and Microtubule Systems
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cell motility is a fundamental process, enabling cells to migrate, for instance during embryogenesis, tissue repair and defense. Force is generated by two protein systems, which also participate in cell proliferation, control macromolecular and organelle distribution and determine the fine structure of the cell interior. The major components of these are actin and tubulin, respectively, and they are referred to as the microfilament and the microtubule systems. This thesis focuses on tropomyosin, one of many microfilament associated proteins coupled to actin dynamics and organization and expressed in several isoform variants. Altered distribution and isoform expression of tropomyosin are signatures of malignant cells and are dealt with in the current thesis. The presence of tropomyosin isoforms in protruding lamellipodia of migrating cells is demonstrated, and a method to fractionate tropomyosin depending on its organization in an easily extractable, and a more tightly bound cytoplasmic form is presented. Analysis of the loosely associated tropomyosin fraction by gel filtration chromatography revealed that most of the tropomyosins in this fraction exist in a multimeric form. It was also observed that the distribution of tropomyosin varied between non-transformed and transformed cells with most of the isoforms enriched in the loosely bound fraction in the latter category of cells. Possibly this reflects the extensive reorganization of the microfilament system observed in cancer cells and which, depending on the context, can be normalized by introduction of certain tropomyosin isoforms.

Many anti-cancer drugs target the microtubule system, inhibit cell division and promote apoptosis. Here it is shown that picropodophyllin, which has promising anticancer properties has a destabilizing effect on microtubules and via the microfilament system causes cells to detach from their substratum. Furthermore, picropodophyllin interferes with stimulation of the insulin-like growth factor receptor, which is involved in growth stimulation, differentiation and survival and whose expression is up-regulated in cancer cells.   

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University, 2009. 44 p.
Keyword
Tropomyosin, Actin, Picropodophyllin, Tubulin, Cell motility, Cancer
National Category
Cell and Molecular Biology
Research subject
Cellbiology
Identifiers
urn:nbn:se:su:diva-27767 (URN)978-91-7155-895-4 (ISBN)
Public defence
2009-06-17, Sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 14-18, Stockholm, 09:30 (English)
Opponent
Supervisors
Available from: 2009-05-27 Created: 2009-05-18 Last updated: 2009-06-04Bibliographically approved

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