| 1. |
- Grenklo, Staffan, et al.
(författare)
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Tropomyosin assembly intermediates in the control of MF-system turnover
- 2008
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Ingår i: European Journal of Cell Biology. - : Elsevier BV. - 0171-9335 .- 1618-1298. ; 87:11, s. 905-920
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Hillberg, Louise, et al.
(författare)
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Tropomyosins are present in lamellipodia of motile cells
- 2006
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Ingår i: European Journal of Cell Biology. - : Elsevier BV. - 0171-9335 .- 1618-1298. ; 85:5, s. 399-409
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Tidskriftsartikel (refereegranskat)abstract
- This paper shows that high-molecular-weight tropomyosins (TMs), as well as shorter isoforms of this protein, are present in significant amounts in lamellipodia and filopodia of spreading normal and transformed cells. The presence of TM in these locales was ascertained by staining of cells with antibodies reacting with endogenous TMs and through the expression of hemaglutinin- and green fluorescent protein-tagged TM isoforms. The observations are contrary to recent reports suggesting the absence of TMs in regions,where polymerization of actin takes place, and indicate that the view of the role of TM in the formation of actin filaments needs to be significantly revised.
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| 3. |
- Nordgren, Niklas, et al.
(författare)
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Oncogene induced stiffening of living cells
- 2015
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Ingår i: Abstracts of Papers of the American Chemical Society. - : AMER CHEMICAL SOC. - 0065-7727. ; 249
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Rathje, Li-Sophie Z., et al.
(författare)
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Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:4, s. 1515-1520
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Tidskriftsartikel (refereegranskat)abstract
- Oncogenes deregulate fundamental cellular functions, which can lead to development of tumors, tumor-cell invasion, and metastasis. As the mechanical properties of cells govern cell motility, we hypothesized that oncogenes promote cell invasion by inducing cytoskeletal changes that increase cellular stiffness. We show that the oncogenes simian virus 40 large T antigen, c-Myc, and cyclin E induce spatial reorganization of the vimentin intermediate filament network in cells. At the cellular level, this reorganization manifests as increased width of vimentin fibers and the collapse of the vimentin network. At nanoscale resolution, the organization of vimentin fibers in these oncogene-expressing cells was more entangled, with increased width of the fibers compared with control cells. Expression of these oncogenes also resulted in up-regulation of the tubulin deacetylase histone deacetylase 6 (HDAC6) and altered spatial distribution of acetylated microtubules. This oncogene expression also induced increases in cellular stiffness and promoted the invasive capacity of the cells. Importantly, HDAC6 was required and sufficient for the structural collapse of the vimentin filament network, and was required for increased cellular stiffness of the oncogene-expressing cells. Taken together, these data are consistent with the possibility that oncogenes can induce cellular stiffness via an HDAC6-induced reorganization of the vimentin intermediate filament network.
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| 5. |
- Zhao Rathje, Li-Sophie, 1971-
(författare)
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A Connection between the Microtubule System and ERK activation;Picropodophyllin, an Inhibitor of the IGF-1 receptor, and IGF-1 Destabilize Microtubules and Activate ERK
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Insulin-like growth factor-1 receptor (IGF-1R) is important for growth and survival of cancer cells, but is not obligatory for growth of normal cells. This has led to attempts to target this receptor to terminate growth of malignant cells. The cyclolignan, picropodophyllin (PPP), has proven useful in inhibiting signalling through the IGF-1R. PPP inhibits IGF-1R autophosphorylation and activation of PI3-kinase/Akt, but it activates ERK in an IGF-1R dependent manner, and causes IGF-1R downregulation. Interestingly, ERK activation and IGF-1R downregulation by IGF-1 and PPP both require ubiquitination of IGF-1R by the E3-ligase Mdm2. In this context, beta-arrestin1 acts as an adapter protein bringing Mdm2 to IGF-1R. How beta-arrestin is recruited to the receptor is unknown. It was recently reported, however, that beta-arrestins bind to microtubules (MT), and that this interaction likely influences signaling via G-protein coupled receptors (GPCRs). This paper reports that the ligand IGF-1 and PPP both have distinct effects on the organization of MT in cultured cells as seen by indirect immunofluorescence, and corroborated by biochemical analysis, demonstrating that IGF-1, as well as PPP, induce MT reorganization and depolymerization. Likely, subsequent association of beta-arrestin1:Mdm2 to the IGF-1R is required for ERK activation, receptor ubiquitination and internalization/downregulation.
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| 6. |
- Zhao Rathje, Li-Sophie, 1971-
(författare)
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Tropomyosin in Normal and Malignant Cells and the Action of Picropodophyllin on the Microfilament and Microtubule Systems
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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