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Yardena Samuels - One of the best experts on this subject based on the ideXlab platform.
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CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma.
Oncotarget, 2018Co-Authors: Michal Alon, Rand Arafeh, Adi Nagler, Tereza Abgarian, Polina Greenberg, Sanna Madan, Eytan Ruppin, Shelly Kalaora, Yardena SamuelsAbstract:// Michal Alon 1 , Rand Arafeh 1 , Joo Sang Lee 2, 3 , Sanna Madan 2, 3 , Shelly Kalaora 1 , Adi Nagler 1 , Tereza Abgarian 1 , Polina Greenberg 1 , Eytan Ruppin 2, 3 and Yardena Samuels 1 1 Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, Israel 2 Center for Bioinformatics and Computational Biology, The University of Maryland, College Park, Maryland, USA 3 Cancer Data Science Lab, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA Correspondence to: Yardena Samuels, email: Yardena.samuels@weizmann.ac.il Keywords: melanoma; NF1; CAPN1; degradation; combination therapy Abbreviations: NF1: Neurofibromin 1; CAPN1: Calpain1 Received: March 07, 2018 Accepted: July 05, 2018 Published: July 27, 2018 ABSTRACT Neurofibromin 1 (NF1), a tumor suppressor that negatively regulates RAS through its GTPase activity, is highly mutated in various types of sporadic human cancers, including melanoma. However, the binding partners of NF1 and the pathways in which it is involved in melanoma have not been characterized in an in depth manner. Utilizing a mass spectrometry analysis of NF1 binding partners, we revealed Calpain1 (CAPN1), a calcium-dependent neutral cysteine protease, as a novel NF1 binding partner that regulates NF1 degradation in melanoma cells. ShRNA-mediated knockdown of CAPN1 or treatment with a CAPN1 inhibitor stabilizes NF1 protein levels, downregulates AKT signaling and melanoma cell growth. Combination treatment of Calpain inhibitor I with MEKi Trametinib in different melanoma cells is more effective in reducing melanoma cell growth compared to treatment with Trametinib alone, suggesting that this combination may have a therapeutic potential in melanoma. This novel mechanism for regulating NF1 in melanoma provides a molecular basis for targeting CAPN1 in order to stabilize NF1 levels and, in doing so, suppressing Ras activation; this mechanism can be exploited therapeutically in melanoma and other cancers.
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CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma.
Oncotarget, 2018Co-Authors: Michal Alon, Rand Arafeh, Adi Nagler, Tereza Abgarian, Polina Greenberg, Sanna Madan, Eytan Ruppin, Shelly Kalaora, Joo Sang Lee, Yardena SamuelsAbstract:Neurofibromin 1 (NF1), a tumor suppressor that negatively regulates RAS through its GTPase activity, is highly mutated in various types of sporadic human cancers, including melanoma. However, the binding partners of NF1 and the pathways in which it is involved in melanoma have not been characterized in an in depth manner. Utilizing a mass spectrometry analysis of NF1 binding partners, we revealed Calpain1 (CAPN1), a calcium-dependent neutral cysteine protease, as a novel NF1 binding partner that regulates NF1 degradation in melanoma cells. ShRNA-mediated knockdown of CAPN1 or treatment with a CAPN1 inhibitor stabilizes NF1 protein levels, downregulates AKT signaling and melanoma cell growth. Combination treatment of Calpain inhibitor I with MEKi Trametinib in different melanoma cells is more effective in reducing melanoma cell growth compared to treatment with Trametinib alone, suggesting that this combination may have a therapeutic potential in melanoma. This novel mechanism for regulating NF1 in melanoma provides a molecular basis for targeting CAPN1 in order to stabilize NF1 levels and, in doing so, suppressing Ras activation; this mechanism can be exploited therapeutically in melanoma and other cancers.
Michal Alon - One of the best experts on this subject based on the ideXlab platform.
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CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma.
Oncotarget, 2018Co-Authors: Michal Alon, Rand Arafeh, Adi Nagler, Tereza Abgarian, Polina Greenberg, Sanna Madan, Eytan Ruppin, Shelly Kalaora, Yardena SamuelsAbstract:// Michal Alon 1 , Rand Arafeh 1 , Joo Sang Lee 2, 3 , Sanna Madan 2, 3 , Shelly Kalaora 1 , Adi Nagler 1 , Tereza Abgarian 1 , Polina Greenberg 1 , Eytan Ruppin 2, 3 and Yardena Samuels 1 1 Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, Israel 2 Center for Bioinformatics and Computational Biology, The University of Maryland, College Park, Maryland, USA 3 Cancer Data Science Lab, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA Correspondence to: Yardena Samuels, email: Yardena.samuels@weizmann.ac.il Keywords: melanoma; NF1; CAPN1; degradation; combination therapy Abbreviations: NF1: Neurofibromin 1; CAPN1: Calpain1 Received: March 07, 2018 Accepted: July 05, 2018 Published: July 27, 2018 ABSTRACT Neurofibromin 1 (NF1), a tumor suppressor that negatively regulates RAS through its GTPase activity, is highly mutated in various types of sporadic human cancers, including melanoma. However, the binding partners of NF1 and the pathways in which it is involved in melanoma have not been characterized in an in depth manner. Utilizing a mass spectrometry analysis of NF1 binding partners, we revealed Calpain1 (CAPN1), a calcium-dependent neutral cysteine protease, as a novel NF1 binding partner that regulates NF1 degradation in melanoma cells. ShRNA-mediated knockdown of CAPN1 or treatment with a CAPN1 inhibitor stabilizes NF1 protein levels, downregulates AKT signaling and melanoma cell growth. Combination treatment of Calpain inhibitor I with MEKi Trametinib in different melanoma cells is more effective in reducing melanoma cell growth compared to treatment with Trametinib alone, suggesting that this combination may have a therapeutic potential in melanoma. This novel mechanism for regulating NF1 in melanoma provides a molecular basis for targeting CAPN1 in order to stabilize NF1 levels and, in doing so, suppressing Ras activation; this mechanism can be exploited therapeutically in melanoma and other cancers.
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CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma.
Oncotarget, 2018Co-Authors: Michal Alon, Rand Arafeh, Adi Nagler, Tereza Abgarian, Polina Greenberg, Sanna Madan, Eytan Ruppin, Shelly Kalaora, Joo Sang Lee, Yardena SamuelsAbstract:Neurofibromin 1 (NF1), a tumor suppressor that negatively regulates RAS through its GTPase activity, is highly mutated in various types of sporadic human cancers, including melanoma. However, the binding partners of NF1 and the pathways in which it is involved in melanoma have not been characterized in an in depth manner. Utilizing a mass spectrometry analysis of NF1 binding partners, we revealed Calpain1 (CAPN1), a calcium-dependent neutral cysteine protease, as a novel NF1 binding partner that regulates NF1 degradation in melanoma cells. ShRNA-mediated knockdown of CAPN1 or treatment with a CAPN1 inhibitor stabilizes NF1 protein levels, downregulates AKT signaling and melanoma cell growth. Combination treatment of Calpain inhibitor I with MEKi Trametinib in different melanoma cells is more effective in reducing melanoma cell growth compared to treatment with Trametinib alone, suggesting that this combination may have a therapeutic potential in melanoma. This novel mechanism for regulating NF1 in melanoma provides a molecular basis for targeting CAPN1 in order to stabilize NF1 levels and, in doing so, suppressing Ras activation; this mechanism can be exploited therapeutically in melanoma and other cancers.
G L Bennett - One of the best experts on this subject based on the ideXlab platform.
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CAPN1 cast and dgat1 genetic effects on preweaning performance carcass quality traits and residual variance of tenderness in a beef cattle population selected for haplotype and allele equalization
Journal of Animal Science, 2014Co-Authors: R G Tait, T L Wheeler, E Casas, John W. Keele, D. A. King, Steven D. Shackelford, Timothy P. L. Smith, G L BennettAbstract:Genetic marker effects and type of inheri- tance are estimated with poor precision when minor marker allele frequencies are low. A stable composite population (MARC III) was subjected to marker-assisted selection for multiple years to equalize specific marker frequencies to 1) estimate effect size and mode of inheri- tance for previously reported SNP on targeted beef car- cass quality traits (n = 254), 2) estimate pleiotropic effects of previously reported SNP on nontarget performance traits (n = 542 or 254), and 3) evaluate tenderness SNP specific residual variance for LM tenderness. Three hap- lotypes within μ-calpain (CAPN1), a SNP in calpastatin (CAST), and a dinucleotide substitution in diacylglycerol O-acyltransferase 1 (DGAT1) were successfully selected to equalize their frequencies. Traits evaluated were birth BW, weaning BW, yearling BW, final BW, dressing per - cent, HCW, fat thickness, LM area, USDA marbling score, yield grade, LM slice shear force (SSF), and vis- ible and near-infrared (VISNIR)-predicted SSF. While the CAPN1 genotype effect on SSF was not significant (P = 0.12), the direction and size of CAPN1 contrasts were consistent with previous research. Effects on SSF between divergent CAPN1 haplotypes (1.153 kg) and the additive effect of CAST (0.902 kg) were large, and animals homozygous for tender alleles at both CAPN1 and CAST would have 4.11 kg lower SSF (27.5% of the mean) than animals homozygous tough for both mark- ers. Furthermore, the interaction between CAPN1 and CAST for SSF was not significant (P = 0.40). There were significant effects for DGAT1 on adjusted fat thick- ness (P = 0.02) and VISNIR-predicted SSF (P < 0.001) with additive and dominance modes of inheritance (P < 0.05) for both traits. Furthermore, CAST genotype spe- cific residual variance models fit significantly better (P < 0.001) than single residual variance models for SSF, with the tougher genotypes having progressively larger residual (and hence phenotypic) variances. Therefore, risk of a tough steak from the undesired CAST geno- type is increased through both an increase in mean and an increase in variation. This work is supportive of the importance of CAPN1 and CAST for mean tenderness in beef, confirms an effect of CAST on beef LM tenderness variation, and identifies an effect of DGAT1 on subcuta- neous fat thickness.
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µ calpain calpastatin and growth hormone receptor genetic effects on preweaning performance carcass quality traits and residual variance of tenderness in angus cattle selected to increase minor haplotype and allele frequencies
Journal of Animal Science, 2014Co-Authors: R G Tait, T L Wheeler, E Casas, D. A. King, R M Thallman, Steven D. Shackelford, Timothy P. L. Smith, G L BennettAbstract:Genetic marker effects and interactions are estimated with poor precision when minor marker allele frequencies are low. An Angus population was subjected to marker assisted selection for multiple years to increase divergent haplotype and minor marker allele frequencies to 1) estimate effect size and mode of inheritance for previously reported SNP on targeted beef carcass quality traits; 2) estimate effects of previously reported SNP on nontarget performance traits; and 3) evaluate tenderness SNP specific residual variance models compared to a single residual variance model for tenderness. Divergent haplotypes within μ-calpain (CAPN1), and SNP within calpastatin (CAST) and growth hormone receptor (GHR) were successfully selected to increase their frequencies. Traits evaluated were birth BW, weaning BW, final BW, fat thickness, LM area, USDA marbling score, yield grade, slice shear force (SSF), and visible and near infrared predicted slice shear force. Both CAPN1 and CAST exhibited additive (P < 0.001) modes of inheritance for SSF and neither exhibited dominance (P ≥ 0.19). Furthermore, the interaction between CAPN1 and CAST for SSF was not significant (P = 0.55). Estimated additive effects of CAPN1 (1.049 kg) and CAST (1.257 kg) on SSF were large in this study. Animals homozygous for tender alleles at both CAPN1 and CAST would have 4.61 kg lower SSF (38.6% of the mean) than animals homozygous tough for both markers. There was also an effect of CAST on yield grade (P < 0.02). The tender CAST allele was associated with more red meat yield and less trimmable fat. There were no significant effects (P ≥ 0.23) for GHR on any of the traits evaluated in this study. Furthermore, CAST specific residual variance models were found to fit significantly better (P < 0.001) than single residual variance models for SSF, with the tougher genotypes having larger residual variance. Thus, the risk of a tough steak from the undesired CAST genotype is increased through both an increase in mean and an increase in variation. This work confirms the importance of CAPN1 and CAST for tenderness in beef, provides a new effect of CAST on beef tenderness, and questions the utility of GHR as a selection marker for beef quality.
Timothy P. L. Smith - One of the best experts on this subject based on the ideXlab platform.
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CAPN1 cast and dgat1 genetic effects on preweaning performance carcass quality traits and residual variance of tenderness in a beef cattle population selected for haplotype and allele equalization
Journal of Animal Science, 2014Co-Authors: R G Tait, T L Wheeler, E Casas, John W. Keele, D. A. King, Steven D. Shackelford, Timothy P. L. Smith, G L BennettAbstract:Genetic marker effects and type of inheri- tance are estimated with poor precision when minor marker allele frequencies are low. A stable composite population (MARC III) was subjected to marker-assisted selection for multiple years to equalize specific marker frequencies to 1) estimate effect size and mode of inheri- tance for previously reported SNP on targeted beef car- cass quality traits (n = 254), 2) estimate pleiotropic effects of previously reported SNP on nontarget performance traits (n = 542 or 254), and 3) evaluate tenderness SNP specific residual variance for LM tenderness. Three hap- lotypes within μ-calpain (CAPN1), a SNP in calpastatin (CAST), and a dinucleotide substitution in diacylglycerol O-acyltransferase 1 (DGAT1) were successfully selected to equalize their frequencies. Traits evaluated were birth BW, weaning BW, yearling BW, final BW, dressing per - cent, HCW, fat thickness, LM area, USDA marbling score, yield grade, LM slice shear force (SSF), and vis- ible and near-infrared (VISNIR)-predicted SSF. While the CAPN1 genotype effect on SSF was not significant (P = 0.12), the direction and size of CAPN1 contrasts were consistent with previous research. Effects on SSF between divergent CAPN1 haplotypes (1.153 kg) and the additive effect of CAST (0.902 kg) were large, and animals homozygous for tender alleles at both CAPN1 and CAST would have 4.11 kg lower SSF (27.5% of the mean) than animals homozygous tough for both mark- ers. Furthermore, the interaction between CAPN1 and CAST for SSF was not significant (P = 0.40). There were significant effects for DGAT1 on adjusted fat thick- ness (P = 0.02) and VISNIR-predicted SSF (P < 0.001) with additive and dominance modes of inheritance (P < 0.05) for both traits. Furthermore, CAST genotype spe- cific residual variance models fit significantly better (P < 0.001) than single residual variance models for SSF, with the tougher genotypes having progressively larger residual (and hence phenotypic) variances. Therefore, risk of a tough steak from the undesired CAST geno- type is increased through both an increase in mean and an increase in variation. This work is supportive of the importance of CAPN1 and CAST for mean tenderness in beef, confirms an effect of CAST on beef LM tenderness variation, and identifies an effect of DGAT1 on subcuta- neous fat thickness.
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µ calpain calpastatin and growth hormone receptor genetic effects on preweaning performance carcass quality traits and residual variance of tenderness in angus cattle selected to increase minor haplotype and allele frequencies
Journal of Animal Science, 2014Co-Authors: R G Tait, T L Wheeler, E Casas, D. A. King, R M Thallman, Steven D. Shackelford, Timothy P. L. Smith, G L BennettAbstract:Genetic marker effects and interactions are estimated with poor precision when minor marker allele frequencies are low. An Angus population was subjected to marker assisted selection for multiple years to increase divergent haplotype and minor marker allele frequencies to 1) estimate effect size and mode of inheritance for previously reported SNP on targeted beef carcass quality traits; 2) estimate effects of previously reported SNP on nontarget performance traits; and 3) evaluate tenderness SNP specific residual variance models compared to a single residual variance model for tenderness. Divergent haplotypes within μ-calpain (CAPN1), and SNP within calpastatin (CAST) and growth hormone receptor (GHR) were successfully selected to increase their frequencies. Traits evaluated were birth BW, weaning BW, final BW, fat thickness, LM area, USDA marbling score, yield grade, slice shear force (SSF), and visible and near infrared predicted slice shear force. Both CAPN1 and CAST exhibited additive (P < 0.001) modes of inheritance for SSF and neither exhibited dominance (P ≥ 0.19). Furthermore, the interaction between CAPN1 and CAST for SSF was not significant (P = 0.55). Estimated additive effects of CAPN1 (1.049 kg) and CAST (1.257 kg) on SSF were large in this study. Animals homozygous for tender alleles at both CAPN1 and CAST would have 4.61 kg lower SSF (38.6% of the mean) than animals homozygous tough for both markers. There was also an effect of CAST on yield grade (P < 0.02). The tender CAST allele was associated with more red meat yield and less trimmable fat. There were no significant effects (P ≥ 0.23) for GHR on any of the traits evaluated in this study. Furthermore, CAST specific residual variance models were found to fit significantly better (P < 0.001) than single residual variance models for SSF, with the tougher genotypes having larger residual variance. Thus, the risk of a tough steak from the undesired CAST genotype is increased through both an increase in mean and an increase in variation. This work confirms the importance of CAPN1 and CAST for tenderness in beef, provides a new effect of CAST on beef tenderness, and questions the utility of GHR as a selection marker for beef quality.
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effects of calpastatin and micro calpain markers in beef cattle on tenderness traits
Journal of Animal Science, 2006Co-Authors: E Casas, T L Wheeler, Stephen N. White, Mohammad Koohmaraie, S D Shackelford, D G Riley, C C Chase, D D Johnson, Timothy P. L. SmithAbstract:The objective of this study was to assess the association of single nucleotide polymorphisms (SNP) developed at the calpastatin (CAST) and mu-calpain (CAPN1) genes with meat tenderness and palatability traits in populations with diverse genetic backgrounds. Three populations were used in the study. One population consisted of Bos taurus that included crossbred animals derived from Hereford, Angus, Red Angus, Limousin, Charolais, Gelbvieh, and Simmental (GPE7; n = 539). Another population consisted of Bos taurus with Bos indicus influence, including crossbred animals from Hereford, Angus, Brangus, Beefmaster, Bonsmara, and Romosinuano (GPE8; n = 580). The third population was Bos indicus and consisted of purebred Brahman (STARS; n = 444). Traits evaluated were meat tenderness measured as Warner-Bratzler shear force (WBSF; kg) at 14 d postmortem, and traits evaluated by trained sensory panels that included tenderness score, juiciness, and flavor intensity. A SNP at the CAST gene had a significant (P < 0.003) effect on WBSF and tenderness score in the GPE7 and GPE8 populations. Animals inheriting the TT genotype at CAST had meat that was more tender than those inheriting the CC genotype. The marker at the CAPN1 gene was significant (P < 0.03) for tenderness score in GPE7 and GPE8. Animals inheriting the CC genotype at CAPN1 had meat that was more tender than those inheriting the TT genotype. Markers at the CAST and CAPN1 genes were associated with flavor intensity in the GPE8 population. Animals inheriting the CC genotype at CAST and the TT genotype at CAPN1 produced steaks with an intense flavor when compared with the other genotypes. An interaction between CAST and CAPN1 was detected (P < 0.05) for WBSF on GPE8. The statistical significance of the interaction is questionable because of the limited number of observations in some cells. Markers developed at the CAST and CAPN1 genes are suitable for use in identifying animals with the genetic potential to produce meat that is more tender.
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A new single nucleotide polymorphism in CAPN1 extends the current tenderness marker test to include cattle of Bos indicus, Bos taurus, and crossbred descent.
Journal of animal science, 2005Co-Authors: Stephen N. White, John W. Keele, Steven D. Shackelford, Mohammad Koohmaraie, C C Chase, D D Johnson, Eduardo Casas, Tommy L. Wheeler, David G. Riley, Timothy P. L. SmithAbstract:The three objectives of this study were to 1) test for the existence of beef tenderness markers in the CAPN1 gene segregating in Brahman cattle; 2) test existing CAPN1 tenderness markers in indicus-influenced crossbred cattle; and 3) produce a revised marker system for use in cattle of all subspecies backgrounds. Previously, two SNP in the CAPN1 gene have been described that could be used to guide selection in Bos taurus cattle (designated Markers 316 and 530), but neither marker segregates at high frequency in Brahman cattle. In this study, we examined three additional SNP in CAPN1 to determine whether variation in this gene could be associated with tenderness in a large, multisire American Brahman population. One marker (termed 4751) was associated with shear force on postmortem d 7 (P < 0.01), 14 (P = 0.015), and 21 (P < 0.001) in this population, demonstrating that genetic variation important for tenderness segregates in Bos indicus cattle at or near CAPN1. Marker 4751 also was associated with shear force (P < 0.01) in the same large, multisire population of cattle of strictly Bos taurus descent that was used to develop the previously reported SNP (referred to as the Germplasm Evaluation [GPE] Cycle 7 population), indicating the possibility that one marker could have wide applicability in cattle of all subspecies backgrounds. To test this hypothesis, Marker 4751 was tested in a third large, multisire cattle population of crossbred subspecies descent (including sire breeds of Brangus, Beefmaster, Bonsmara, Romosinuano, Hereford, and Angus referred to as the GPE Cycle 8 population). The highly significant association of Marker 4751 with shear force in this population (P < 0.001) confirms the usefulness of Marker 4751 in cattle of all subspecies backgrounds, including Bos taurus, Bos indicus, and crossbred descent. This wide applicability adds substantial value over previously released Markers 316 and 530. However, Marker 316, which had previously been shown to be associated with tenderness in the GPE Cycle 7 population, also was highly associated with shear force in the GPE Cycle 8 animals (P < 0.001). Thus, Marker 316 may continue to be useful in a variety of populations with a high percentage of Bos taurus backgrounds. An optimal marker strategy for CAPN1 in many cases will be to use both Markers 316 and 4751.
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Bovine CAPN1 maps to a region of BTA29 containing a quantitative trait locus for meat tenderness.
Journal of animal science, 2000Co-Authors: Timothy P. L. Smith, Caird E. Rexroad, Eduardo Casas, Steven M. Kappes, John W. KeeleAbstract:Micromolar calcium activated neural protease (CAPN1) was investigated as a potential candidate gene for a quantitative trait locus (QTL) on BTA29 affecting meat tenderness. A 2,948-bp bovine cDNA containing the entire coding region of the gene was obtained, showing 91% identity to human CAPN1. The 716 AA protein predicted from this sequence shows 97% similarity (95% identity) to the 714 AA human protein. Analysis of the gene structure revealed that CAPN1 mRNA is encoded by at least 19 exons, and 11,055 bp of the gene were sequenced, including 17 introns. Two single nucleotide polymorphisms (SNP) were detected in intron 12 and were used to map bovine CAPN1 to the telomeric end of the BTA29 linkage group. This approximately coincides with the position of the QTL, demonstrating that CAPN1 protease is a positional candidate gene potentially affecting variation in meat tenderness in a bovine resource mapping population.
Shelly Kalaora - One of the best experts on this subject based on the ideXlab platform.
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CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma.
Oncotarget, 2018Co-Authors: Michal Alon, Rand Arafeh, Adi Nagler, Tereza Abgarian, Polina Greenberg, Sanna Madan, Eytan Ruppin, Shelly Kalaora, Yardena SamuelsAbstract:// Michal Alon 1 , Rand Arafeh 1 , Joo Sang Lee 2, 3 , Sanna Madan 2, 3 , Shelly Kalaora 1 , Adi Nagler 1 , Tereza Abgarian 1 , Polina Greenberg 1 , Eytan Ruppin 2, 3 and Yardena Samuels 1 1 Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, Israel 2 Center for Bioinformatics and Computational Biology, The University of Maryland, College Park, Maryland, USA 3 Cancer Data Science Lab, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA Correspondence to: Yardena Samuels, email: Yardena.samuels@weizmann.ac.il Keywords: melanoma; NF1; CAPN1; degradation; combination therapy Abbreviations: NF1: Neurofibromin 1; CAPN1: Calpain1 Received: March 07, 2018 Accepted: July 05, 2018 Published: July 27, 2018 ABSTRACT Neurofibromin 1 (NF1), a tumor suppressor that negatively regulates RAS through its GTPase activity, is highly mutated in various types of sporadic human cancers, including melanoma. However, the binding partners of NF1 and the pathways in which it is involved in melanoma have not been characterized in an in depth manner. Utilizing a mass spectrometry analysis of NF1 binding partners, we revealed Calpain1 (CAPN1), a calcium-dependent neutral cysteine protease, as a novel NF1 binding partner that regulates NF1 degradation in melanoma cells. ShRNA-mediated knockdown of CAPN1 or treatment with a CAPN1 inhibitor stabilizes NF1 protein levels, downregulates AKT signaling and melanoma cell growth. Combination treatment of Calpain inhibitor I with MEKi Trametinib in different melanoma cells is more effective in reducing melanoma cell growth compared to treatment with Trametinib alone, suggesting that this combination may have a therapeutic potential in melanoma. This novel mechanism for regulating NF1 in melanoma provides a molecular basis for targeting CAPN1 in order to stabilize NF1 levels and, in doing so, suppressing Ras activation; this mechanism can be exploited therapeutically in melanoma and other cancers.
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CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma.
Oncotarget, 2018Co-Authors: Michal Alon, Rand Arafeh, Adi Nagler, Tereza Abgarian, Polina Greenberg, Sanna Madan, Eytan Ruppin, Shelly Kalaora, Joo Sang Lee, Yardena SamuelsAbstract:Neurofibromin 1 (NF1), a tumor suppressor that negatively regulates RAS through its GTPase activity, is highly mutated in various types of sporadic human cancers, including melanoma. However, the binding partners of NF1 and the pathways in which it is involved in melanoma have not been characterized in an in depth manner. Utilizing a mass spectrometry analysis of NF1 binding partners, we revealed Calpain1 (CAPN1), a calcium-dependent neutral cysteine protease, as a novel NF1 binding partner that regulates NF1 degradation in melanoma cells. ShRNA-mediated knockdown of CAPN1 or treatment with a CAPN1 inhibitor stabilizes NF1 protein levels, downregulates AKT signaling and melanoma cell growth. Combination treatment of Calpain inhibitor I with MEKi Trametinib in different melanoma cells is more effective in reducing melanoma cell growth compared to treatment with Trametinib alone, suggesting that this combination may have a therapeutic potential in melanoma. This novel mechanism for regulating NF1 in melanoma provides a molecular basis for targeting CAPN1 in order to stabilize NF1 levels and, in doing so, suppressing Ras activation; this mechanism can be exploited therapeutically in melanoma and other cancers.
