Tropomyosin: The path from cell architecture and signalling to cancer therapy
Дата: 9 июня 2014 г.
МГУ, Биологический факультет, ауд. 359, 17:00
Peter Gunning
School of Medical Sciences, University of New South Wales, Kensington, Australia
Tropomyosin: The path from cell architecture and signalling to cancer therapy
All organisms from bacteria to plants and animals have evolved the capacity to generate multiple ‘actin’ filaments which differ in their composition and perform functionally distinct roles within the cell. All animals sort both their actin and tropomyosin isoforms to different locations within a single cell. This sorting often correlates with known specialised actin filament functions within the cell. Sorting is often more easily detected within differentiated cells. Sorting appears to be the result of local assembly and is maintained by the integrity of local filaments and higher order structures. Most recently we have identified a second tropomyosin associated with the Golgi and two tropomyosins almost exclusively located in the lamaellipodium. We have also found that 70-90% of phalloidin-positive pixels in stained cells are also positive for tropomyosin indicating that the majority of actin filaments in the cytoskeleton are likely to contain tropomyosin. Tropomyosin isoforms are engaged in a broad range of isoform-specific functions. Recent work has focussed on the cancerassociated tropomyosin Tm5NM1. All known tumour cells retain Tm5NM1 and cancer progression is usually associated with reductions in the levels of most Tm’s except Tm5NM1. Atomic Force Microscopy has been used to show that Tm5NM1 can increase cell stiffness to a level substantially greater than other isoforms. Mice which over-express Tm5NM1 display increases in the sizes of specific tissues and organs whereas the gene knockout has the converse result. The levels of Tm5NM1 regulate glucose uptake into tissues, possibly via the role of Tm5NM1-containing actin filaments in the exocyst complex. Previous studies have shown that tropomyosin isoforms can regulate the interaction of actin filaments with actin binding proteins and motors in an isoform specific manner and that tropomyosin is limiting for actin filament accumulation in cell culture. More recent data has shown in mice that tropomyosin supply is limiting for actin filament levels in vivo. In addition, the levels of Tm5NM1 can regulate the levels of exocyst components Sec8 and Myo1c in vivo. This correlates with previous work indicating that the steady state levels of tropomyosin isoforms can determine the steady state levels and activity of actin binding proteins and motors in cell culture. The cancer-associated Tm5NM1 is the only tropomyosin which promotes cell proliferation and this activity may relate to its impact on tissue and organ size. Mouse embryo fibroblasts which over-express or are knocked out for Tm5NM1 display reciprocal effects on cell proliferation. Knockout cells show reduced proliferation as a result of a defect in the canonical MAPK pathway. This is due to complete shutdown of ERKII regulation of cell proliferation. Recent data indicates that Tm5NM1 actin filaments are absolutely required for nuclearsignal-dependent nuclear translocation of ERKII. In addition, further data indicates that other products of the TPM3 gene are required for embryonic stem cell differentiation and the TPM4 gene is required for normal senescence. This suggests that tropomyosins may be able to regulate different signalling pathways in an isoform specific manner. We have recently published the development of anti-Tm5NM1 drugs for the treatment of cancer. Drug treatment leads to the disassembly of the tumour cell actin cytoskeleton but does not impact striated muscle or differentiated cells in culture.
Справки: 8-495-939-5528
moscellbiol@gmail.com
web-site: https://sites.google.com/site/moscellbios/
МГУ, Биологический факультет, ауд. 359, 17:00
Peter Gunning
School of Medical Sciences, University of New South Wales, Kensington, Australia
Tropomyosin: The path from cell architecture and signalling to cancer therapy
All organisms from bacteria to plants and animals have evolved the capacity to generate multiple ‘actin’ filaments which differ in their composition and perform functionally distinct roles within the cell. All animals sort both their actin and tropomyosin isoforms to different locations within a single cell. This sorting often correlates with known specialised actin filament functions within the cell. Sorting is often more easily detected within differentiated cells. Sorting appears to be the result of local assembly and is maintained by the integrity of local filaments and higher order structures. Most recently we have identified a second tropomyosin associated with the Golgi and two tropomyosins almost exclusively located in the lamaellipodium. We have also found that 70-90% of phalloidin-positive pixels in stained cells are also positive for tropomyosin indicating that the majority of actin filaments in the cytoskeleton are likely to contain tropomyosin. Tropomyosin isoforms are engaged in a broad range of isoform-specific functions. Recent work has focussed on the cancerassociated tropomyosin Tm5NM1. All known tumour cells retain Tm5NM1 and cancer progression is usually associated with reductions in the levels of most Tm’s except Tm5NM1. Atomic Force Microscopy has been used to show that Tm5NM1 can increase cell stiffness to a level substantially greater than other isoforms. Mice which over-express Tm5NM1 display increases in the sizes of specific tissues and organs whereas the gene knockout has the converse result. The levels of Tm5NM1 regulate glucose uptake into tissues, possibly via the role of Tm5NM1-containing actin filaments in the exocyst complex. Previous studies have shown that tropomyosin isoforms can regulate the interaction of actin filaments with actin binding proteins and motors in an isoform specific manner and that tropomyosin is limiting for actin filament accumulation in cell culture. More recent data has shown in mice that tropomyosin supply is limiting for actin filament levels in vivo. In addition, the levels of Tm5NM1 can regulate the levels of exocyst components Sec8 and Myo1c in vivo. This correlates with previous work indicating that the steady state levels of tropomyosin isoforms can determine the steady state levels and activity of actin binding proteins and motors in cell culture. The cancer-associated Tm5NM1 is the only tropomyosin which promotes cell proliferation and this activity may relate to its impact on tissue and organ size. Mouse embryo fibroblasts which over-express or are knocked out for Tm5NM1 display reciprocal effects on cell proliferation. Knockout cells show reduced proliferation as a result of a defect in the canonical MAPK pathway. This is due to complete shutdown of ERKII regulation of cell proliferation. Recent data indicates that Tm5NM1 actin filaments are absolutely required for nuclearsignal-dependent nuclear translocation of ERKII. In addition, further data indicates that other products of the TPM3 gene are required for embryonic stem cell differentiation and the TPM4 gene is required for normal senescence. This suggests that tropomyosins may be able to regulate different signalling pathways in an isoform specific manner. We have recently published the development of anti-Tm5NM1 drugs for the treatment of cancer. Drug treatment leads to the disassembly of the tumour cell actin cytoskeleton but does not impact striated muscle or differentiated cells in culture.
Справки: 8-495-939-5528
moscellbiol@gmail.com
web-site: https://sites.google.com/site/moscellbios/