The Experts below are selected from a list of 1929 Experts worldwide ranked by ideXlab platform
Andreas Bikfalvi - One of the best experts on this subject based on the ideXlab platform.
-
The TYRP1-Tag/TYRP1-FGFR1-DN Bigenic Mouse A Model for Selective Inhibition of Tumor Development, Angiogenesis, and Invasion into the Neural Tissue by Blockade of Fibroblast Growth Factor Receptor Activity
Cancer Research, 2004Co-Authors: Benoit Rousseau, Frederic Larrieu-lahargue, Sophie Javerzat, Frédéric Guilhem-ducléon, Andreas BikfalviAbstract:We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. TYRP1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with TYRP1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in TYRP1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when TYRP1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the TYRP1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.
-
the TYRP1 tag TYRP1 fgfr1 dn bigenic mouse a model for selective inhibition of tumor development angiogenesis and invasion into the neural tissue by blockade of fibroblast growth factor receptor activity
Cancer Research, 2004Co-Authors: Benoit Rousseau, Sophie Javerzat, Frederic Larrieulahargue, Frederic Guilhemducleon, Andreas BikfalviAbstract:We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. TYRP1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with TYRP1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in TYRP1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when TYRP1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the TYRP1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.
Vijayasaradhi Setaluri - One of the best experts on this subject based on the ideXlab platform.
-
Selective down‐regulation of tyrosinase family gene TYRP1 by inhibition of the activity of melanocyte transcription factor, MITF
Nucleic Acids Research, 2002Co-Authors: Douglas D. Fang, Yoshiaki Tsuji, Vijayasaradhi SetaluriAbstract:Tyrosinase (TYR), tyrosinase-related protein-1 (TYRP1/gp75) and dopachrome tautomerase (DCT/ TYRP2) belong to a family of melanocyte-specific gene products involved in melanin pigmentation. During melanocyte development expression of tyrosinase family genes is thought to be orchestrated in part by the binding of a shared basic helix‐loop‐helix transcription factor MITF to the M box, a regulatory element conserved among these genes. In transformed melanocytes, expression of tyrosinase and TYRPs is highly variable. Whereas TYR expression in melanoma cells is regulated by both transcriptional and post-translational mechanisms, TYRP1/gp75 transcription is often completely extinguished during melanoma tumor progression. In this study, we investigated the mechanisms of selective repression of TYRP1 transcription. Interestingly, in early stage melanoma cells TYRP1 mRNA could be induced by inhibition of protein synthesis. Transient transfection experiments with a minimal TYRP1 promoter showed that the promoter activity correlates with expression of the endogenous TYRP1 gene. Nucleotide deletion analysis revealed novel regulatory sequences that attenuate the M box-dependent MITF activity, but which are not involved in the repression of TYRP1. Gel mobility shift analysis showed that binding of the transcription factor MITF to the TYRP1 M box is selectively inhibited in TYRP1 ‐ cells. These data suggest that protein factors that modulate the activity of MITF in melanoma cells repress TYRP1 and presumably other MITF target genes.
-
selective down regulation of tyrosinase family gene TYRP1 by inhibition of the activity of melanocyte transcription factor mitf
Nucleic Acids Research, 2002Co-Authors: Douglas D. Fang, Yoshiaki Tsuji, Vijayasaradhi SetaluriAbstract:Tyrosinase (TYR), tyrosinase-related protein-1 (TYRP1/gp75) and dopachrome tautomerase (DCT/ TYRP2) belong to a family of melanocyte-specific gene products involved in melanin pigmentation. During melanocyte development expression of tyrosinase family genes is thought to be orchestrated in part by the binding of a shared basic helix‐loop‐helix transcription factor MITF to the M box, a regulatory element conserved among these genes. In transformed melanocytes, expression of tyrosinase and TYRPs is highly variable. Whereas TYR expression in melanoma cells is regulated by both transcriptional and post-translational mechanisms, TYRP1/gp75 transcription is often completely extinguished during melanoma tumor progression. In this study, we investigated the mechanisms of selective repression of TYRP1 transcription. Interestingly, in early stage melanoma cells TYRP1 mRNA could be induced by inhibition of protein synthesis. Transient transfection experiments with a minimal TYRP1 promoter showed that the promoter activity correlates with expression of the endogenous TYRP1 gene. Nucleotide deletion analysis revealed novel regulatory sequences that attenuate the M box-dependent MITF activity, but which are not involved in the repression of TYRP1. Gel mobility shift analysis showed that binding of the transcription factor MITF to the TYRP1 M box is selectively inhibited in TYRP1 ‐ cells. These data suggest that protein factors that modulate the activity of MITF in melanoma cells repress TYRP1 and presumably other MITF target genes.
Vincent J. Hearing - One of the best experts on this subject based on the ideXlab platform.
-
Direct interaction of tyrosinase with TYRP1 to form heterodimeric complexes in vivo.
Journal of cell science, 2007Co-Authors: Takeshi Kobayashi, Vincent J. HearingAbstract:Mutations of the critical and rate-limiting melanogenic enzyme tyrosinase (Tyr) result in hypopigmentation of the hair, skin and eyes. Two other related enzymes, TYRP1 and Dct, catalyze distinct post-Tyr reactions in melanin biosynthesis. Tyr, TYRP1 and Dct have been proposed to interact with and stabilize each other in multi-enzyme complexes, and in vitro, Tyr activity is more stable in the presence of TYRP1 and/or Dct. We recently reported that Tyr is degraded more quickly in mutant TYRP1 mouse melanocytes than in wild-type TYRP1 melanocytes, and that decreased stability of Tyr can be partly rescued by infection with wild-type TYRP1. Although interactions between Tyr and TYRP1 have been demonstrated in vitro, there is no direct evidence for Tyr interaction with TYRP1 in vivo. In this study, we use in vivo chemical crosslinking to stabilize the association of Tyr with other cellular proteins. Western blot analysis revealed that TYRP1, but not Dct, associates with Tyr in murine melanocytes in vivo, and more specifically, in melanosomes. Two-dimensional SDS-PAGE analysis detected heterodimeric species of Tyr and TYRP1. Taken together, these data demonstrate that TYRP1 interacts directly with Tyr in vivo, which may regulate the stability and trafficking of melanogenic enzymes and thus pigment synthesis.
-
oculocutaneous albinism types 1 and 3 are er retention diseases mutation of tyrosinase or TYRP1 can affect the processing of both mutant and wild type proteins
The FASEB Journal, 2001Co-Authors: Kazutomo Toyofuku, Ikuo Wada, Julio C Valencia, Tsuneto Kushimoto, Victor J Ferrans, Vincent J. HearingAbstract:Various types of oculocutaneous albinism (OCA) are associated with reduced pigmentation in the skin, hair, and eyes that results from mutations in genes involved in melanin synthesis. Immortal mouse melanocyte lines (melan-a, melan-b, and melan-c) provide opportune models with which to investigate the etiology of two different types of OCA (types I and III), which arise from mutations in Tyr and TYRP1, respectively. We compared intracellular processing, sorting, and degradation of tyrosinase and TYRP1, and the effects on their catalytic function and melanin synthesis, in these wild-type and mutant melanocytes. A mutation in either Tyr or TYRP1 increased the time of association of tyrosinase and TYRP1 with calnexin and Bip, which in turn resulted in the retention of these mutant products in the ER. A mutation in either gene selectively enhanced the duration and efficiency of chaperone interactions (even with the wild-type protein in the mutant melanocytes) and markedly slowed their transport to melanosomes...
-
oculocutaneous albinism types 1 and 3 are er retention diseases mutation of tyrosinase or TYRP1 can affect the processing of both mutant and wild type proteins
The FASEB Journal, 2001Co-Authors: Kazutomo Toyofuku, Ikuo Wada, Julio C Valencia, Tsuneto Kushimoto, Victor J Ferrans, Vincent J. HearingAbstract:Various types of oculocutaneous albinism (OCA) are associated with reduced pigmentation in the skin, hair, and eyes that results from mutations in genes involved in melanin synthesis. Immortal mouse melanocyte lines (melan-a, melan-b, and melan-c) provide opportune models with which to investigate the etiology of two different types of OCA (types I and III), which arise from mutations in Tyr and TYRP1, respectively. We compared intracellular processing, sorting, and degradation of tyrosinase and TYRP1, and the effects on their catalytic function and melanin synthesis, in these wild-type and mutant melanocytes. A mutation in either Tyr or TYRP1 increased the time of association of tyrosinase and TYRP1 with calnexin and Bip, which in turn resulted in the retention of these mutant products in the ER. A mutation in either gene selectively enhanced the duration and efficiency of chaperone interactions (even with the wild-type protein in the mutant melanocytes) and markedly slowed their transport to melanosomes. These results show that OCA1 and OCA3 are (in some cases, at least) ER retention diseases wherein a mutation in one melanogenic protein affects the maturation and stability of the other in the melanogenic pathway.
-
Tyrosinase Stabilization by TYRP1 (the brown Locus Protein)
Journal of Biological Chemistry, 1998Co-Authors: Takeshi Kobayashi, Dorothy C. Bennett, Genji Imokawa, Vincent J. HearingAbstract:Mammalian melanogenesis is regulated directly or indirectly by over 85 distinct loci. The Tyr/albino locus, in which mutations cause a lack of pigmentation, encodes tyrosinase (Tyr), the critical and rate-limiting melanogenic enzyme. Other melanogenic enzymes include TYRP1 (or TRP1) and 3,4-dihydroxyphenylalanine-chrome tautomerase (Dct or TRP2) encoded at the TYRP1/brown and Dct/slaty loci, respectively. Murine TYRP1 can oxidize 5, 6-dihydroxyindole-2-carboxylic acid (DHICA) produced by Dct, but mutations in TYRP1 also affect the catalytic functions of Tyr. All three enzymes are membrane-bound melanosomal proteins with similar structural features and are thought to interact within and stabilize a melanogenic complex. We have now further investigated the effect of a TYRP1(b) mutation on Tyr stability. Pulse/chase labeling experiments show that Tyr is degraded more quickly in TYRP1(b) mutant melanocytes than in melanocytes wild type at that locus. This reduced stability of Tyr can be partly rescued by infection with the wild type TYRP1 gene, and this is accompanied by phenotypic rescue of infected melanocytes. In sum, these results suggest that, in addition to its catalytic function in oxidizing DHICA, TYRP1 may play an important role in stabilizing Tyr, a second potential role in the regulation of melanin formation.
Malgorzata Czyz - One of the best experts on this subject based on the ideXlab platform.
-
TYRP1 mrna level is stable and mitf m independent in drug naive vemurafenib and trametinib resistant braf v600e melanoma cells
Archives of Dermatological Research, 2020Co-Authors: Mariusz L. Hartman, Malgorzata CzyzAbstract:TYRP1 mRNA is of interest due to its potential non-coding role as a sponge sequestering tumor-suppressive miRs in melanoma. To our knowledge, there is no report on changes in TYRP1 expression in melanomas after development of resistance to targeted therapies. We used patient-derived drug-naive RASQ61R and BRAFV600E melanoma cell lines. In BRAFV600E melanoma cells, resistance to vemurafenib and trametinib was developed. A time-lapse fluorescence microscope was used to rate proliferation, qRT-PCR and Western blotting were used to assess TYRP1 expression and MITF-M level and activity. A high TYRP1 protein level in RASQ61R cells corresponded with high TYRP1 mRNA level, whereas undetectable TYRP1 protein in BRAFV600E cells was accompanied by medium mRNA level, also in cells carrying NF1R135W variant in addition. TYRP1 expression was MITF-M-independent, since similar transcript status was found in MITF-Mhigh and MITF-Mlow cells. For the first time, we showed that TYRP1 expression remained unaltered in melanoma cells that became resistant to vemurafenib or trametinib, including those cells losing MITF-M. Also drug discontinuation in resistant cells did not substantially affect TYRP1 expression. To verify in vitro results, publicly available microarray data were analyzed. TYRP1 transcript levels stay unaltered in the majority of paired melanoma samples from patients before treatment and after relapse caused by resistance to targeted therapies. As TYRP1 mRNA level remains unaltered in melanoma cells during development of resistance to vemurafenib or trametinib, therapies developed to terminate a sponge activity of TYRP1 transcript may be extended to patients that relapse with resistant disease.
-
TYRP1 mRNA level is stable and MITF-M-independent in drug-naïve, vemurafenib- and trametinib-resistant BRAFV600E melanoma cells.
Archives of Dermatological Research, 2019Co-Authors: Mariusz L. Hartman, Malgorzata CzyzAbstract:TYRP1 mRNA is of interest due to its potential non-coding role as a sponge sequestering tumor-suppressive miRs in melanoma. To our knowledge, there is no report on changes in TYRP1 expression in melanomas after development of resistance to targeted therapies. We used patient-derived drug-naive RASQ61R and BRAFV600E melanoma cell lines. In BRAFV600E melanoma cells, resistance to vemurafenib and trametinib was developed. A time-lapse fluorescence microscope was used to rate proliferation, qRT-PCR and Western blotting were used to assess TYRP1 expression and MITF-M level and activity. A high TYRP1 protein level in RASQ61R cells corresponded with high TYRP1 mRNA level, whereas undetectable TYRP1 protein in BRAFV600E cells was accompanied by medium mRNA level, also in cells carrying NF1R135W variant in addition. TYRP1 expression was MITF-M-independent, since similar transcript status was found in MITF-Mhigh and MITF-Mlow cells. For the first time, we showed that TYRP1 expression remained unaltered in melanoma cells that became resistant to vemurafenib or trametinib, including those cells losing MITF-M. Also drug discontinuation in resistant cells did not substantially affect TYRP1 expression. To verify in vitro results, publicly available microarray data were analyzed. TYRP1 transcript levels stay unaltered in the majority of paired melanoma samples from patients before treatment and after relapse caused by resistance to targeted therapies. As TYRP1 mRNA level remains unaltered in melanoma cells during development of resistance to vemurafenib or trametinib, therapies developed to terminate a sponge activity of TYRP1 transcript may be extended to patients that relapse with resistant disease.
Benoit Rousseau - One of the best experts on this subject based on the ideXlab platform.
-
The TYRP1-Tag/TYRP1-FGFR1-DN Bigenic Mouse A Model for Selective Inhibition of Tumor Development, Angiogenesis, and Invasion into the Neural Tissue by Blockade of Fibroblast Growth Factor Receptor Activity
Cancer Research, 2004Co-Authors: Benoit Rousseau, Frederic Larrieu-lahargue, Sophie Javerzat, Frédéric Guilhem-ducléon, Andreas BikfalviAbstract:We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. TYRP1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with TYRP1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in TYRP1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when TYRP1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the TYRP1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.
-
the TYRP1 tag TYRP1 fgfr1 dn bigenic mouse a model for selective inhibition of tumor development angiogenesis and invasion into the neural tissue by blockade of fibroblast growth factor receptor activity
Cancer Research, 2004Co-Authors: Benoit Rousseau, Sophie Javerzat, Frederic Larrieulahargue, Frederic Guilhemducleon, Andreas BikfalviAbstract:We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. TYRP1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with TYRP1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in TYRP1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when TYRP1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the TYRP1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.
