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Izumi Nakashima - One of the best experts on this subject based on the ideXlab platform.
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linkage between Melanocytic Tumor development and early burst of ret protein expression for tolerance induction in metallothionein i ret transgenic mouse lines
Oncogene, 1999Co-Authors: Masashi Kato, Masaharu Ohbayashi, Masahide Takahashi, Anwarul A Akhand, Toyonori Tuzuki, Haruhiko Suzuki, Kenichi Isobe, Izumi NakashimaAbstract:We examined the basis of the all or none difference in inducing Melanocytic Tumor development among three transgenic mouse lines (304, 192 and 242) to which the same promoter-enhancer (metallothionein-I) and oncogene (ret) were introduced. We initially demonstrated that both skin melanosis and Ret protein expression in skin, thymus and brain first became detectable before or immediately after birth in the mice of the Tumor developing lines (304 and 192), whereas they became detectable a few days after birth in the mice of the non-Tumor developing line (242) by Western blotting and immunohistochemical analysis. Interestingly, the Ret protein expression in skin developed rapidly after birth as a burst with peak levels on 0.5 – 1.5 day newborns of lines 304 and 192 and on 7.0 – 7.5 day-old mice of line 242. The levels of autophosphorylation of Ret kinase in skin were, however, invariable among these three transgenic mouse lines. The mice of line 242, but not those of lines 192 and 304, responded to Ret protein immunization by increased antigen-dependent lymphocyte proliferation and T-cell-mediated Tumor growth suppression in vitro. Furthermore, ret-transgenic mice of line 242, but not line 304, rejected the subcutaneously transplanted Tumors that had originally developed in a mouse of line 304. These results suggest that whether oncogene product-specific-tolerance is established or not to antiTumor immunity may be decided by the dynamics of ret oncogene expression before and after delivery and this is the primary factor determining development or non-development of melanoma.
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differential regulation of mmp 9 and timp 2 expression in malignant melanoma developed in metallothionein ret transgenic mice
Japanese Journal of Cancer Research, 1999Co-Authors: Masami Asai, Izumi Nakashima, Masashi Kato, Naoya Asai, Toshihide Iwashita, Hideki Murakami, Kumi Kawai, Masahide TakahashiAbstract:We recently established a metallothionein-I(MT)/RET transgenic mouse line in which skin melanosis, benign Melanocytic Tumor and malignant melanoma develop stepwise. Malignant melanoma cells but not benign Melanocytic Tumor cells had metastatic ability in transgenic mice. In the present study, we investigated the expression of several matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs), including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MT1– MMP, TIMP-1 and TIMP-2, in these Tumors. Western and northern blot analyses revealed that malignant transformation of Melanocytic Tumors developed in MT/RET transgenic mice accompanied with upregulation of MMP-9 and downregulation of TIMP-2. Expression of other MMP and TIMP genes examined was very low or undetectable in both benign and malignant Tumors. Since activation of MMP-9 in malignant Tumors was detected by gelatin zymography, these results suggest that imbalance of expression of the MMP-9 and TIMP-2 genes might be associated with metastatic ability of melanoma cells developed in MT/RET transgenic mice.
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Establishment and characterization of a malignant Melanocytic Tumor cell line expressing the ret oncogene.
Oncogene, 1992Co-Authors: Masahiko Taniguchi, Takashi Iwamoto, Izumi Nakashima, Nakayama A, Masaharu Ohbayashi, Mutsushi Matsuyama, Masahide TakahashiAbstract:We established a cell line (designated Mel-ret) from a Melanocytic Tumor developed in a metallothionein/ret transgenic mouse. Unlike primary Melanocytic Tumors, which did not show malignant features, when the Mel-ret cells were transplanted into nude mice they invaded into surrounding tissues and had metastatic ability. Although the Ret proteins were expressed at similar levels in the cell line and the primary Tumors, the level of tyrosine phosphorylation in the Mel-ret cells was much higher than that in the primary Tumors. In particular, an 85-kDa tyrosine-phosphorylated band was specifically detected in the Mel-ret cells. These results suggest that the increase in tyrosine phosphorylation may be responsible for malignant transformation of the Mel-ret cells. Immunofluorescence and cell fractionation studies showed that the Ret proteins and most of tyrosine-phosphorylated proteins in the Mel-ret cells localized in the membrane fraction. No activation of phosphatidyl-inositol-3 kinase (PI-3 kinase), a target protein for several tyrosine kinases, was detected in the Mel-ret cells.
Masahide Takahashi - One of the best experts on this subject based on the ideXlab platform.
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linkage between Melanocytic Tumor development and early burst of ret protein expression for tolerance induction in metallothionein i ret transgenic mouse lines
Oncogene, 1999Co-Authors: Masashi Kato, Masaharu Ohbayashi, Masahide Takahashi, Anwarul A Akhand, Toyonori Tuzuki, Haruhiko Suzuki, Kenichi Isobe, Izumi NakashimaAbstract:We examined the basis of the all or none difference in inducing Melanocytic Tumor development among three transgenic mouse lines (304, 192 and 242) to which the same promoter-enhancer (metallothionein-I) and oncogene (ret) were introduced. We initially demonstrated that both skin melanosis and Ret protein expression in skin, thymus and brain first became detectable before or immediately after birth in the mice of the Tumor developing lines (304 and 192), whereas they became detectable a few days after birth in the mice of the non-Tumor developing line (242) by Western blotting and immunohistochemical analysis. Interestingly, the Ret protein expression in skin developed rapidly after birth as a burst with peak levels on 0.5 – 1.5 day newborns of lines 304 and 192 and on 7.0 – 7.5 day-old mice of line 242. The levels of autophosphorylation of Ret kinase in skin were, however, invariable among these three transgenic mouse lines. The mice of line 242, but not those of lines 192 and 304, responded to Ret protein immunization by increased antigen-dependent lymphocyte proliferation and T-cell-mediated Tumor growth suppression in vitro. Furthermore, ret-transgenic mice of line 242, but not line 304, rejected the subcutaneously transplanted Tumors that had originally developed in a mouse of line 304. These results suggest that whether oncogene product-specific-tolerance is established or not to antiTumor immunity may be decided by the dynamics of ret oncogene expression before and after delivery and this is the primary factor determining development or non-development of melanoma.
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differential regulation of mmp 9 and timp 2 expression in malignant melanoma developed in metallothionein ret transgenic mice
Japanese Journal of Cancer Research, 1999Co-Authors: Masami Asai, Izumi Nakashima, Masashi Kato, Naoya Asai, Toshihide Iwashita, Hideki Murakami, Kumi Kawai, Masahide TakahashiAbstract:We recently established a metallothionein-I(MT)/RET transgenic mouse line in which skin melanosis, benign Melanocytic Tumor and malignant melanoma develop stepwise. Malignant melanoma cells but not benign Melanocytic Tumor cells had metastatic ability in transgenic mice. In the present study, we investigated the expression of several matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs), including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MT1– MMP, TIMP-1 and TIMP-2, in these Tumors. Western and northern blot analyses revealed that malignant transformation of Melanocytic Tumors developed in MT/RET transgenic mice accompanied with upregulation of MMP-9 and downregulation of TIMP-2. Expression of other MMP and TIMP genes examined was very low or undetectable in both benign and malignant Tumors. Since activation of MMP-9 in malignant Tumors was detected by gelatin zymography, these results suggest that imbalance of expression of the MMP-9 and TIMP-2 genes might be associated with metastatic ability of melanoma cells developed in MT/RET transgenic mice.
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Establishment and characterization of a malignant Melanocytic Tumor cell line expressing the ret oncogene.
Oncogene, 1992Co-Authors: Masahiko Taniguchi, Takashi Iwamoto, Izumi Nakashima, Nakayama A, Masaharu Ohbayashi, Mutsushi Matsuyama, Masahide TakahashiAbstract:We established a cell line (designated Mel-ret) from a Melanocytic Tumor developed in a metallothionein/ret transgenic mouse. Unlike primary Melanocytic Tumors, which did not show malignant features, when the Mel-ret cells were transplanted into nude mice they invaded into surrounding tissues and had metastatic ability. Although the Ret proteins were expressed at similar levels in the cell line and the primary Tumors, the level of tyrosine phosphorylation in the Mel-ret cells was much higher than that in the primary Tumors. In particular, an 85-kDa tyrosine-phosphorylated band was specifically detected in the Mel-ret cells. These results suggest that the increase in tyrosine phosphorylation may be responsible for malignant transformation of the Mel-ret cells. Immunofluorescence and cell fractionation studies showed that the Ret proteins and most of tyrosine-phosphorylated proteins in the Mel-ret cells localized in the membrane fraction. No activation of phosphatidyl-inositol-3 kinase (PI-3 kinase), a target protein for several tyrosine kinases, was detected in the Mel-ret cells.
Masashi Kato - One of the best experts on this subject based on the ideXlab platform.
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linkage between Melanocytic Tumor development and early burst of ret protein expression for tolerance induction in metallothionein i ret transgenic mouse lines
Oncogene, 1999Co-Authors: Masashi Kato, Masaharu Ohbayashi, Masahide Takahashi, Anwarul A Akhand, Toyonori Tuzuki, Haruhiko Suzuki, Kenichi Isobe, Izumi NakashimaAbstract:We examined the basis of the all or none difference in inducing Melanocytic Tumor development among three transgenic mouse lines (304, 192 and 242) to which the same promoter-enhancer (metallothionein-I) and oncogene (ret) were introduced. We initially demonstrated that both skin melanosis and Ret protein expression in skin, thymus and brain first became detectable before or immediately after birth in the mice of the Tumor developing lines (304 and 192), whereas they became detectable a few days after birth in the mice of the non-Tumor developing line (242) by Western blotting and immunohistochemical analysis. Interestingly, the Ret protein expression in skin developed rapidly after birth as a burst with peak levels on 0.5 – 1.5 day newborns of lines 304 and 192 and on 7.0 – 7.5 day-old mice of line 242. The levels of autophosphorylation of Ret kinase in skin were, however, invariable among these three transgenic mouse lines. The mice of line 242, but not those of lines 192 and 304, responded to Ret protein immunization by increased antigen-dependent lymphocyte proliferation and T-cell-mediated Tumor growth suppression in vitro. Furthermore, ret-transgenic mice of line 242, but not line 304, rejected the subcutaneously transplanted Tumors that had originally developed in a mouse of line 304. These results suggest that whether oncogene product-specific-tolerance is established or not to antiTumor immunity may be decided by the dynamics of ret oncogene expression before and after delivery and this is the primary factor determining development or non-development of melanoma.
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differential regulation of mmp 9 and timp 2 expression in malignant melanoma developed in metallothionein ret transgenic mice
Japanese Journal of Cancer Research, 1999Co-Authors: Masami Asai, Izumi Nakashima, Masashi Kato, Naoya Asai, Toshihide Iwashita, Hideki Murakami, Kumi Kawai, Masahide TakahashiAbstract:We recently established a metallothionein-I(MT)/RET transgenic mouse line in which skin melanosis, benign Melanocytic Tumor and malignant melanoma develop stepwise. Malignant melanoma cells but not benign Melanocytic Tumor cells had metastatic ability in transgenic mice. In the present study, we investigated the expression of several matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs), including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MT1– MMP, TIMP-1 and TIMP-2, in these Tumors. Western and northern blot analyses revealed that malignant transformation of Melanocytic Tumors developed in MT/RET transgenic mice accompanied with upregulation of MMP-9 and downregulation of TIMP-2. Expression of other MMP and TIMP genes examined was very low or undetectable in both benign and malignant Tumors. Since activation of MMP-9 in malignant Tumors was detected by gelatin zymography, these results suggest that imbalance of expression of the MMP-9 and TIMP-2 genes might be associated with metastatic ability of melanoma cells developed in MT/RET transgenic mice.
Masaharu Ohbayashi - One of the best experts on this subject based on the ideXlab platform.
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linkage between Melanocytic Tumor development and early burst of ret protein expression for tolerance induction in metallothionein i ret transgenic mouse lines
Oncogene, 1999Co-Authors: Masashi Kato, Masaharu Ohbayashi, Masahide Takahashi, Anwarul A Akhand, Toyonori Tuzuki, Haruhiko Suzuki, Kenichi Isobe, Izumi NakashimaAbstract:We examined the basis of the all or none difference in inducing Melanocytic Tumor development among three transgenic mouse lines (304, 192 and 242) to which the same promoter-enhancer (metallothionein-I) and oncogene (ret) were introduced. We initially demonstrated that both skin melanosis and Ret protein expression in skin, thymus and brain first became detectable before or immediately after birth in the mice of the Tumor developing lines (304 and 192), whereas they became detectable a few days after birth in the mice of the non-Tumor developing line (242) by Western blotting and immunohistochemical analysis. Interestingly, the Ret protein expression in skin developed rapidly after birth as a burst with peak levels on 0.5 – 1.5 day newborns of lines 304 and 192 and on 7.0 – 7.5 day-old mice of line 242. The levels of autophosphorylation of Ret kinase in skin were, however, invariable among these three transgenic mouse lines. The mice of line 242, but not those of lines 192 and 304, responded to Ret protein immunization by increased antigen-dependent lymphocyte proliferation and T-cell-mediated Tumor growth suppression in vitro. Furthermore, ret-transgenic mice of line 242, but not line 304, rejected the subcutaneously transplanted Tumors that had originally developed in a mouse of line 304. These results suggest that whether oncogene product-specific-tolerance is established or not to antiTumor immunity may be decided by the dynamics of ret oncogene expression before and after delivery and this is the primary factor determining development or non-development of melanoma.
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Establishment and characterization of a malignant Melanocytic Tumor cell line expressing the ret oncogene.
Oncogene, 1992Co-Authors: Masahiko Taniguchi, Takashi Iwamoto, Izumi Nakashima, Nakayama A, Masaharu Ohbayashi, Mutsushi Matsuyama, Masahide TakahashiAbstract:We established a cell line (designated Mel-ret) from a Melanocytic Tumor developed in a metallothionein/ret transgenic mouse. Unlike primary Melanocytic Tumors, which did not show malignant features, when the Mel-ret cells were transplanted into nude mice they invaded into surrounding tissues and had metastatic ability. Although the Ret proteins were expressed at similar levels in the cell line and the primary Tumors, the level of tyrosine phosphorylation in the Mel-ret cells was much higher than that in the primary Tumors. In particular, an 85-kDa tyrosine-phosphorylated band was specifically detected in the Mel-ret cells. These results suggest that the increase in tyrosine phosphorylation may be responsible for malignant transformation of the Mel-ret cells. Immunofluorescence and cell fractionation studies showed that the Ret proteins and most of tyrosine-phosphorylated proteins in the Mel-ret cells localized in the membrane fraction. No activation of phosphatidyl-inositol-3 kinase (PI-3 kinase), a target protein for several tyrosine kinases, was detected in the Mel-ret cells.
G.n.p. Van Muijen - One of the best experts on this subject based on the ideXlab platform.
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decreased expression of both the low density lipoprotein receptor related protein alpha 2 macroglobulin receptor and its receptor associated protein in late stages of cutaneous Melanocytic Tumor progression
Cancer Research, 1996Co-Authors: T.j. De Vries, D.j. Ruiter, J H Verheijen, A C W De Bart, Ulrich H Weidle, G.n.p. Van MuijenAbstract:We recently found that the proteins of the proteolytic system of plasminogen activation emerge in late stages of Melanocytic Tumor progression. A large body of evidence suggests a role for two proteins, the low-density lipoprotein receptor-related protein (LRP)/α2-macroglobulin receptor and its receptor-associated protein (RAP), in the internalization of components of the plasminogen activation system. Here, we present data on the presence of these two proteins in human melanoma cell lines which differ in metastatic capacity, their corresponding xenografts, and in cutaneous Melanocytic lesions. With flow cytometry, we found surface expression of LRP to be restricted to urokinase plasminogen activator, producing highly metastatic cell lines. These cell lines also produce higher levels of LRP mRNA, whereas RAP mRNA and protein are expressed at equal levels in all cell lines and not expressed at the cell surface. Xenografts of cell lines producing high levels of LRP remarkably contain only a small fraction of LRP-positive Tumor cells. Using immunohistochemistry on frozen sections of 107 human Melanocytic lesions comprising the various stages of Melanocytic Tumor progression, we found that expression of both LRP and RAP decreased in Tumor progression. Furthermore, we noted that LRP and RAP are coexpressed within the same lesion. Using immunofluorescence double staining, we found that LRP and RAP colocalize in the same cells in the lesions studied and in the same cell structures in the cell lines studied. In conclusion, our results indicate that LRP and RAP are coordinately expressed in a decreased fashion in Melanocytic Tumor progression. Based on the staining results in xenografts and in human Melanocytic lesions, we conclude that a strong correlation between expression of LRP and urokinase-type plasminogen activator seems not to exist in in vivo melanomas. Chemicals/CAS: LDL-Receptor Related Protein 1; Neoplasm Proteins; Receptors, Immunologic; Receptors, LDL; RNA, Messenger
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The plasminogen activation system in melanoma cell lines and in Melanocytic lesions.
Melanoma Research, 1996Co-Authors: T.j. De Vries, G.n.p. Van Muijen, D.j. RuiterAbstract:A large body of evidence suggests a role for the proteolytic plasminogen activation system in invasion and metastatic spread of Tumor cells including melanoma cells. Plasminogen activation by human melanoma cell lines and B16 mouse melanoma cell lines has been extensively studied. Apart from expression of urokinase-type plasminogen activator, melanoma cells differ from cells derived from other Tumors in the abundant expression of tissue-type plasminogen activator. The possible role of both types of plasminogen activator in metastatic spread of melanoma cells is discussed. In recent years the localization of mRNAs and proteins of the plasminogen activation system and of related proteins in cutaneous Melanocytic Tumor progression has been well documented. A possible mechanism for migration of melanoma cells in vivo is suggested.
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plasminogen activators their inhibitors and urokinase receptor emerge in late stages of Melanocytic Tumor progression
American Journal of Pathology, 1994Co-Authors: T.j. De Vries, D.j. Ruiter, J H Verheijen, Ulrich H Weidle, Paul H A Quax, M Denijn, K N Verrijp, H W Verspaget, G.n.p. Van MuijenAbstract:Degradation of the extracellular matrix and other tissue barriers by proteases like plasminogen activators (PAs) is a prerequisite for neoplastic growth and metastasis. Recently, we reported that highly metastatic behavior of human melanoma cells in nude mice correlates with urokinase-type PA (u-PA) expression and activity and with PA inhibitor type 1 and 2 (PAI-1, PAI-2) expression. Here we report on the occurrence of components of the PA system in the various stages of human melanoma Tumor progression in situ. We studied the protein distribution on freshly frozen lesions of common nevocellular nevi (n = 25), dysplastic (= atypical) nevi (n = 16), early primary melanomas (n = 8), advanced primary melanomas (n = 11), and melanoma metastases (n = 17). Tissue-type PA was present in endothelial cells in all lesions, whereas in metastases it could be detected in Tumor cells in a minority of the lesions. u-PA, its receptor, PAI-1, and PAI-2 could not be detected in benign and in early stages but appeared frequently in advanced primary melanoma and melanoma metastasis lesions. u-PA was detected in stromal cells and in Tumor cells at the invasive front, the u-PA receptor and PAI-2 in Tumor cells, and PAI-1 in the extracellular matrix surrounding Tumor cells. Localization of the corresponding messenger RNAs and enzyme activities revealed a similar distribution. We conclude that plasminogen activation is a late event in melanoma Tumor progression.