The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Eric A Pierce - One of the best experts on this subject based on the ideXlab platform.
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biallelic RP1 associated retinal dystrophies expanding the mutational and clinical spectrum
Molecular Vision, 2020Co-Authors: Rachel M Huckfeldt, Eric A Pierce, Florin Grigorian, Emily Place, Jason Comander, Demetrios G Vavvas, Lucy H Young, Paul Yang, Maria Shurygina, Mark E PennesiAbstract:Purpose To evaluate the phenotypic spectrum of autosomal recessive RP1-associated retinal dystrophies and assess genotypic associations. Methods A retrospective multicenter study was performed of patients with biallelic RP1-associated retinal dystrophies. Data including presenting symptoms and age, visual acuity, kinetic perimetry, full field electroretinogram, fundus examination, multimodal retinal imaging, and RP1 genotype were evaluated. Results Nineteen eligible patients from 17 families were identified and ranged in age from 10 to 56 years at the most recent evaluation. Ten of the 21 unique RP1 variants identified were novel, and mutations within exon 2 accounted for nearly half of alleles across the cohort. Patients had clinical diagnoses of retinitis pigmentosa (13), cone-rod dystrophy (3), Leber congenital amaurosis (1), early-onset severe retinal dystrophy (1), and macular dystrophy (1). Macular atrophy was a common feature across the cohort. Symptom onset occurred between 4 and 30 years of age (mean 14.9 years, median 13 years), but there were clusters of onset age that correlated with the effects of RP1 mutations at a protein level. Patients with later-onset disease, including retinitis pigmentosa, had at least one missense variant in an exon 2 DCX domain. Conclusions Biallelic RP1 mutations cause a broad spectrum of retinal disease. Exon 2 missense mutations are a significant contributor to disease and can be associated with a considerably later onset of retinitis pigmentosa than that typically associated with biallelic RP1 mutations.
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a murine RP1 missense mutation causes protein mislocalization and slowly progressive photoreceptor degeneration
American Journal of Pathology, 2014Co-Authors: Delu Song, Ying Song, Eric A Pierce, Steve Grieco, Yafeng Li, Allan A Hunter, L Zhao, Robert A Deangelis, Patsy M NishinaAbstract:Mutations in the RP1 gene can cause retinitis pigmentosa. We identified a spontaneous L66P mutation caused by two adjacent point mutations in the RP1 gene in a colony of C57BL/6J mice. Mice homozygous for the L66P mutation exhibited slow, progressive photoreceptor degeneration throughout their lifespan. Optical coherence tomography imaging found abnormal photoreceptor reflectivity at 1 month of age. Histology found shortening and disorganization of the photoreceptor inner and outer segments and progressive thinning of the outer nuclear layer. Electroretinogram a- and b-wave amplitudes were decreased with age. Western blot analysis found that the quantity and size of the mutated retinitis pigmentosa 1 (RP1) protein were normal. However, immunohistochemistry found that the mutant RP1 protein partially mislocalized to the transition zone of the shortened axonemes. This mutation disrupted colocalization with cytoplasmic microtubules in vitro. In conclusion, the L66P mutation in the first doublecortin domain of the RP1 gene impairs RP1 protein localization and function, leading to abnormalities in photoreceptor outer segment structure and progressive photoreceptor degeneration. This is the first missense mutation in RP1 shown to cause retinal degeneration. It provides a unique, slowly progressive photoreceptor degeneration model that mirrors the slow degeneration kinetics in most patients with retinitis pigmentosa.
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expression of wild type RP1 protein in RP1 knock in mice rescues the retinal degeneration phenotype
PLOS ONE, 2012Co-Authors: Rob W J Collin, Frans P M Cremers, Anneke Den I Hollander, Ingeborgh L Van Den Born, Eric A PierceAbstract:Mutations in the retinitis pigmentosa 1 (RP1) gene are a common cause of autosomal dominant retinitis pigmentosa (adRP), and have also been found to cause autosomal recessive RP (arRP) in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39) are located in the 4th and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3rd exon of RP1 (c.686delC; p.P229QfsX35) found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated RP1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as RP1 transgenic mice carrying a wild-type BAC RP1 transgene. The RP1-Q662X allele produces a truncated RP1 protein, and homozygous RP1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of RP1 protein from the BAC transgene without removal of the mutant RP1-Q662X protein. Over-expression of RP1 protein in additional BAC RP1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated RP1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled.
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the retinitis pigmentosa 1 protein is a photoreceptor microtubule associated protein
The Journal of Neuroscience, 2004Co-Authors: Eric A PierceAbstract:The outer segments of rod and cone photoreceptor cells are highly specialized sensory cilia made up of hundreds of membrane discs stacked into an orderly array along the photoreceptor axoneme. It is not known how the alignment of the outer segment discs is controlled, although it has been suggested that the axoneme may play a role in this process. Mutations in the retinitis pigmentosa 1 (RP1) gene are a common cause of retinitis pigmentosa (RP). Disruption of the RP1 gene in mice causes misorientation of outer segment discs, suggesting a role for RP1 in outer segment organization. Here, we show that the RP1 protein is part of the photoreceptor axoneme. Amino acids 28-228 of RP1, which share limited homology with the microtubule-binding domains of the neuronal microtubule-associated protein (MAP) doublecortin, mediate the interaction between RP1 and microtubules, indicating that the putative doublecortin (DCX) domains in RP1 are functional. The N-terminal portion of RP1 stimulates the formation of microtubules in vitro and stabilizes cytoplasmic microtubules in heterologous cells. Evaluation of photoreceptor axonemes from mice with targeted disruptions of the RP1 gene shows that RP1 proteins that contain the DCX domains also help control axoneme length and stability in vivo. These results demonstrate that RP1 is a MAP. Given the specific expression of RP1 in photoreceptors, RP1 is thus the first photoreceptor-specific MAP to be identified. Furthermore, these findings indicate that the RP1 form of inherited retinal degeneration is part of the larger class of neurodegenerative diseases caused by MAP dysfunction.
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progressive photoreceptor degeneration outer segment dysplasia and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa 1 RP1 gene
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Kyeongmi Cheon, Eric A Pierce, Steven Nusinowitz, Karen Atkins, Asif Azimi, Stephen P Daiger, Debora B Farber, John R Heckenlively, Lori S SullivanAbstract:Retinitis pigmentosa (RP), a common group of human retinopathic diseases, is characterized by late-onset night blindness, loss of peripheral vision, and diminished or absent electroretinogram (ERG) responses. Mutations in the photoreceptor-specific gene RP1 account for 5–10% of cases of autosomal dominant RP. We generated a mouse model of the RP1 form of RP by targeted disruption of the mouse ortholog (RP1) of human RP1. In RP1−/− mice, the number of rod photoreceptors decreased progressively over a period of 1 year, whereas that of cone photoreceptors did not change for at least 10 months. Light and electron microscopic analysis revealed that outer segments of RP1−/− rods and cones were morphologically abnormal and became progressively shorter in length. Before photoreceptor cell death, rhodopsin was mislocalized in inner segments and cell bodies of RP1−/− rods. Rod ERG amplitudes of RP1−/− mice were significantly smaller than those of RP1+/+ mice over a period of 12 months, whereas those of RP1+/− mice were intermediate. The decreases in cone ERG amplitudes were slower and less severe than those in rods. These findings demonstrate that RP1 is required for normal morphogenesis of photoreceptor outer segments and also may play a role in rhodopsin transport to the outer segments. The phenotype of RP1 mutant mice resembles the human RP1 disease. Thus, these mice provide a useful model for studies of RP1 function, disease pathology, and therapeutic interventions.
Scot H Hulbert - One of the best experts on this subject based on the ideXlab platform.
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recombinant RP1 genes confer necrotic or nonspecific resistance phenotypes
Molecular Genetics and Genomics, 2010Co-Authors: Shavannor M Smith, Martin Steinau, Harold N Trick, Scot H HulbertAbstract:Genes at the RP1 rust resistance locus of maize confer race-specific resistance to the common rust fungus Puccinia sorghi. Three variant genes with nonspecific effects (HRP1 -Kr1N, -D*21 and -MD*19) were found to be generated by intragenic crossing over within the LRR region. The LRR region of most NBS-LRR encoding genes is quite variable and codes for one of the regions in resistance gene proteins that controls specificity. Sequence comparisons demonstrated that the RP1-Kr1N recombinant gene was identical to the N-terminus of the RP1-kp2 gene and C-terminus of another gene from its HRP1-K grandparent. The RP1-D*21 recombinant gene consists of the N-terminus of the RP1-dp2 gene and C-terminus of the RP1-D gene from the parental haplotype. Similarly, a recombinant gene from the RP1-MD*19 haplotype has the N-terminus of an RP1 gene from the HRP1-M parent and C-terminus of the RP1-D19 gene from the HRP1-D parent. The recombinant RP1 -Kr1N, -D*21 and -MD*19 genes activated defense responses in the absence of their AVR proteins triggering HR (hypersensitive response) in the absence of the pathogen. The results indicate that the frequent intragenic recombination events that occur in the RP1 gene cluster not only recombine the genes into novel haplotypes, but also create genes with nonspecific effects. Some of these may contribute to nonspecific quantitative resistance but others have severe consequences for the fitness of the plant.
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allelic and haplotypic diversity at the RP1 rust resistance locus of maize
Genetics, 2004Co-Authors: Shavannor M Smith, Anthony J Pryor, Scot H HulbertAbstract:The maize RP1 rust resistance locus is a complex consisting of a family of closely related resistance genes. The number of RP1 paralogs in different maize lines (haplotypes) varied from a single gene in some stocks of the inbred A188 to >50 genes in haplotypes carrying the RP1-A and RP1-H specificities. The sequences of paralogs in unrelated haplotypes differ, indicating that the genetic diversity of RP1-related genes is extremely broad in maize. Two unrelated haplotypes with five or nine paralogs had identical resistance phenotypes (RP1-D) encoded in genes that differed by three nucleotides resulting in a single amino acid substitution. Genes in some haplotypes are more similar to each other than to any of the genes in other haplotypes indicating that they are evolving in a concerted fashion.
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aberrant mrna processing of the maize RP1 d rust resistance gene in wheat and barley
Molecular Plant-microbe Interactions, 2004Co-Authors: Michael Ayliffe, Martin Steinau, Harold N Trick, Scot H Hulbert, R F Park, Lee Rooke, Maria G Pacheco, Anthony J PryorAbstract:The maize RP1-D gene confers race-specific resistance against Puccinia sorghi (common leaf rust) isolates containing a corresponding avrRP1-D avirulence gene. An RP1-D genomic clone and a similar RP1-D transgene regulated by the maize ubiquitin promoter were transformed independently into susceptible maize lines and shown to confer RP1-D resistance, demonstrating that this resistance can be transferred as a single gene. Transfer of these functional transgenes into wheat and barley did not result in novel resistances when these plants were challenged with isolates of wheat stem rust (P. graminis), wheat leaf rust (P. triticina), or barley leaf rust (P. hordei). Regardless of the promoter employed, low levels of gene expression were observed. When constitutive promoters were used for transgene expression, a majority of RP1-D transcripts were truncated in the nucleotide binding site-encoding region by premature polyadenylation. This aberrant mRNA processing was unrelated to gene function because an inactive ...
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recombination between paralogues at the RP1 rust resistance locus in maize
Genetics, 2001Co-Authors: Nicholas C Collins, Shavannor M Smith, Michael Ayliffe, Jeff Drake, Tony Pryor, Scot H HulbertAbstract:RP1 is a complex rust resistance locus of maize. The HRP1-D haplotype is composed of RP1-D and eight paralogues, seven of which also code for predicted nucleotide binding site-leucine rich repeat (NBS-LRR) proteins similar to the RP1-D gene. The paralogues are polymorphic (DNA identities 91-97%), especially in the C-terminal LRR domain. The remaining family member encodes a truncated protein that has no LRR domain. Seven of the nine family members, including the truncated gene, are transcribed. Sequence comparisons between paralogues provide evidence for past recombination events between paralogues and diversifying selection, particularly in the C-terminal half of the LRR domain. Variants selected for complete or partial loss of RP1-D resistance can be explained by unequal crossing over that occurred mostly within coding regions. The RP1-D gene is altered or lost in all variants, the recombination breakpoints occur throughout the genes, and most recombinant events (9/14 examined) involved the same untranscribed paralogue with the RP1-D gene. One recombinant with a complete LRR from RP1-D, but the amino-terminal portion from another homologue, conferred the RP1-D specificity but with a reduced level of resistance.
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resistance genes in the RP1 region of maize effective against puccinia sorghi virulent on the RP1 d gene in north america
Plant Disease, 2001Co-Authors: Jerald K Pataky, Molly C Pate, Scot H HulbertAbstract:ABSTRACT Resistance in sweet corn conferred by the RP1-D gene has controlled common rust, caused by Puccinia sorghi, in North American corn for nearly 15 years. Eleven isolates of P. sorghi virulent on corn with the RP1-D gene were collected from Rp-resistant corn in 1999 from Wiscon-sin, Illinois, New York, and Minnesota. Isolates were increased on susceptible sweet corn. Urediniospores of nine isolates were bulked. Reactions of individual Rp genes in the RP1 region and reactions of linked combinations of Rp genes in the RP1 region (i.e., compound rust resistance genes) were evaluated against the bulked population of P. sorghi in several greenhouse trials. Reactions of individual and compound Rp genes also were evaluated against individual isolates of P. sorghi. Each trial contained at least two replicates of several lines with Rp genes and one susceptible check. Five to 10 two-leaved seedlings per line were inoculated at least twice with a suspension of urediniospores. Ten days after inoculation, rust r...
Qiong Huang - One of the best experts on this subject based on the ideXlab platform.
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IGFBP-RP1 suppresses epithelial–mesenchymal transition and metastasis in colorectal cancer
Cell Death and Disease, 2015Co-Authors: Jianbin Zhang, Wenjing Ruan, Fangying Xu, Enping Xu, Yu Ma, Qiong HuangAbstract:Epithelial–mesenchymal transition (EMT) was initially recognized during organogenesis and has recently been reported to be involved in promoting cancer invasion and metastasis. Cooperation of transforming growth factor-β (TGF-β) and other signaling pathways, such as Ras and Wnt, is essential to inducing EMT, but the molecular mechanisms remain to be fully determined. Here, we reported that insulin-like growth factor binding protein-related protein 1 (IGFBP-RP1), a potential tumor suppressor, controls EMT in colorectal cancer progression. We revealed the inhibitory role of IGFBP-RP1 through analyses of clinical colorectal cancer samples and various EMT and metastasis models in vitro and in vivo. Moreover, we demonstrated that IGFBP-RP1 suppresses EMT and tumor metastasis by repressing TGF-β-mediated EMT through the Smad signaling cascade. These data establish that IGFBP-RP1 functions as a suppressor of EMT and metastasis in colorectal cancer.
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igfbp RP1 suppresses epithelial mesenchymal transition and metastasis in colorectal cancer
Cell Death and Disease, 2015Co-Authors: Jing Zhang, Wenjing Ruan, Fangying Xu, Enping Xu, Qiong HuangAbstract:Epithelial–mesenchymal transition (EMT) was initially recognized during organogenesis and has recently been reported to be involved in promoting cancer invasion and metastasis. Cooperation of transforming growth factor-β (TGF-β) and other signaling pathways, such as Ras and Wnt, is essential to inducing EMT, but the molecular mechanisms remain to be fully determined. Here, we reported that insulin-like growth factor binding protein-related protein 1 (IGFBP-RP1), a potential tumor suppressor, controls EMT in colorectal cancer progression. We revealed the inhibitory role of IGFBP-RP1 through analyses of clinical colorectal cancer samples and various EMT and metastasis models in vitro and in vivo. Moreover, we demonstrated that IGFBP-RP1 suppresses EMT and tumor metastasis by repressing TGF-β-mediated EMT through the Smad signaling cascade. These data establish that IGFBP-RP1 functions as a suppressor of EMT and metastasis in colorectal cancer.
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tumor suppressor gene insulin like growth factor binding protein related protein 1 igfbp RP1 induces senescence like growth arrest in colorectal cancer cells
Experimental and Molecular Pathology, 2008Co-Authors: Bingjian Lu, Wenjing Ruan, Hongqiang Wang, Hu Hu, Hong Deng, Qiong HuangAbstract:Abstract Insulin-like growth factor binding protein-related protein 1 (IGFBP-RP1) is a potential tumor suppressor gene. This study attempted to explore a potential senescence-like role for IGFBP-RP1 in suppressing human colorectal cancer. Recombinant IGFBP-RP1 inhibited cell proliferation and induced G1 cell cycle arrest in RKO and CW2 cells. It induced a senescence-like phenotype by showing 2-fold higher β-galactosidase activity in IGFBP-RP1-transfectants over that in control cells. Western blot confirmed down-regulation of phosphorylated retinoblastoma protein (pRB) and up-regulation of p53 in IGFBP-RP1-transfectants as compared with control cells. Thus, IGFBP-RP1 might be a key molecule in the cellular senescence pathway. Our results uncovered a novel molecular mechanism involving the altered expression of pRB and p53 for tumor suppressor gene IGFBP-RP1 in colorectal cancer. Restoration of IGFBP-RP1 function might have potential therapeutic significance in colorectal cancer.
Ron G Rosenfeld - One of the best experts on this subject based on the ideXlab platform.
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insulin resistance is associated with increased serum concentration of igf binding protein related protein 1 igfbp RP1 mac25
Diabetes, 2006Co-Authors: Abel Lopezbermejo, Javad Khosravi, Jose Manuel Fernandezreal, Katherine L Pratt, Roser Casamitjana, Maria Garciagil, Ron G Rosenfeld, Wifredo RicartAbstract:IGF-binding protein (IGFBP)-related protein 1 (IGFBP-RP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-RP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [ S i ] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [ K ITT ] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-RP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-RP1 exhibited decreased S i and adiponectin (both P P P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-RP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-RP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-RP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S i , sTNFR2, and age stood as independent predictive variables of IGFBP-RP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-RP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-RP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-RP1 and the IGF system in humans.
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Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-RP1/MAC25).
Diabetes, 2006Co-Authors: Abel López-bermejo, Javad Khosravi, Katherine L Pratt, Roser Casamitjana, Ron G Rosenfeld, José Manuel Fernández-real, Maria García-gil, Wifredo RicartAbstract:IGF-binding protein (IGFBP)-related protein 1 (IGFBP-RP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-RP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [ S i ] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [ K ITT ] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-RP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-RP1 exhibited decreased S i and adiponectin (both P P P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-RP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-RP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-RP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S i , sTNFR2, and age stood as independent predictive variables of IGFBP-RP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-RP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-RP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-RP1 and the IGF system in humans.
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generation of anti insulin like growth factor binding protein related protein 1 igfbp RP1 mac25 monoclonal antibodies and immunoassay quantification of igfbp RP1 in human serum and distribution in human fluids and tissues
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Abel Lopezbermejo, Javad Khosravi, Christopher L Corless, Radha G Krishna, Anastasia Diamandi, Umesh Bodani, Eric M Kofoed, Donna L Graham, Ron G RosenfeldAbstract:The IGF-binding protein (IGFBP)-related proteins (rPs) are a group of recently described cysteine-rich proteins that share significant amino-terminal structural similarity with the conventional IGFBPs. IGFBP-RP1 (also known as MAC25/angiomodulin/prostacyclin-stimulating factor and T1A12), regulates cellular proliferation, adhesion, and angiogenesis and stimulates prostacyclin synthesis. We characterized new monoclonal antibodies generated against IGFBP-RP1 and have used them to study the distribution of IGFBP-RP1 in human biological fluids and tissues. Additionally, we have developed a noncompetitive sandwich-type immunoassay to quantitate the concentrations of IGFBP-RP1 in human serum. IGFBP-RP1 was readily detectable in serum, urine, amniotic fluid, and cerebrospinal fluid by immunoblot analysis. Evaluation of the newly developed immunoassay demonstrated acceptable analytical performance, with a detection limit of 0.7 μg/liter, a dynamic range of 3.1–100 μg/liter, and intra- and interassay coefficients ...
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Generation of anti-insulin-like growth factor-binding protein-related protein 1 (IGFBP-RP1/MAC25) monoclonal antibodies and immunoassay: quantification of IGFBP-RP1 in human serum and distribution in human fluids and tissues.
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Abel López-bermejo, Javad Khosravi, Christopher L Corless, Radha G Krishna, Anastasia Diamandi, Umesh Bodani, Eric M Kofoed, Donna L Graham, Ron G RosenfeldAbstract:The IGF-binding protein (IGFBP)-related proteins (rPs) are a group of recently described cysteine-rich proteins that share significant amino-terminal structural similarity with the conventional IGFBPs. IGFBP-RP1 (also known as MAC25/angiomodulin/prostacyclin-stimulating factor and T1A12), regulates cellular proliferation, adhesion, and angiogenesis and stimulates prostacyclin synthesis. We characterized new monoclonal antibodies generated against IGFBP-RP1 and have used them to study the distribution of IGFBP-RP1 in human biological fluids and tissues. Additionally, we have developed a noncompetitive sandwich-type immunoassay to quantitate the concentrations of IGFBP-RP1 in human serum. IGFBP-RP1 was readily detectable in serum, urine, amniotic fluid, and cerebrospinal fluid by immunoblot analysis. Evaluation of the newly developed immunoassay demonstrated acceptable analytical performance, with a detection limit of 0.7 μg/liter, a dynamic range of 3.1–100 μg/liter, and intra- and interassay coefficients ...
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insulin like growth factor binding protein related protein 1 igfbp RP1 is a potential tumor suppressor protein for prostate cancer
Cancer Research, 1999Co-Authors: Cynthia C Sprenger, Ron G Rosenfeld, Susan E Damon, Stephen R PlymateAbstract:Insulin-like growth factor binding protein-related protein-1 (IGFBP-RP1) has been shown to have decreased expression in the progression from benign to malignant prostate epithelial cells (V. Hwa et al., J. Clin Endocrinol. Metab., 83: 4355–4362, 1998). The present study was undertaken to determine the effects of the re-expression of IGFBP-RP1 in a cell line from a model of human prostate cancer, M12, in which IGFBP-RP1 expression had been demonstrated to decrease from the parent epithelial cell, P69, to the malignant subline, M12. An IGFBP-RP1 cDNA encoding the protein was transfected into M12 cells in a plasmid that resulted in constitutive-expression of IGFBP-RP1. Clones of transfected M12 cells were selected for low (L) and high (H) levels of expression, and the plasmid vector alone was transfected into M12 as a control. After transfection, there was a marked alteration in the morphology of the M12 cells such that the H clones had an elongated appearance when compared with the M12 control cells. The M12 clones overexpressing IGFBP-RP1 had a dose-related increase in population doubling time, decreased colony formation in soft agar, an increased propensity to undergo apoptosis in response to 6-hydroxyurea, and decreased tumor formation in male athymic, nude mice. These data suggest that IGFBP-RP1 may have a suppressive effect on prostate cancer development.
Peter J Balintkurti - One of the best experts on this subject based on the ideXlab platform.
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maize homologs of ccoaomt and hct two key enzymes in lignin biosynthesis form complexes with the nlr RP1 protein to modulate the defense response
Plant Physiology, 2016Co-Authors: Guanfeng Wang, Peter J BalintkurtiAbstract:Disease resistance ( R ) genes encode nucleotide binding Leu-rich-repeat (NLR) proteins that confer resistance to specific pathogens. Upon pathogen recognition they trigger a defense response that usually includes a so-called hypersensitive response (HR), a rapid localized cell death at the site of pathogen infection. Intragenic recombination between two maize ( Zea mays ) NLRs, RP1-D and RP1-dp2, resulted in the formation of a hybrid NLR, RP1-D21, which confers an autoactive HR in the absence of pathogen infection. From a previous quantitative trait loci and genome-wide association study, we identified genes encoding two key enzymes in lignin biosynthesis, hydroxycinnamoyltransferase (HCT) and caffeoyl CoA O -methyltransferase (CCoAOMT), adjacent to the nucleotide polymorphisms that were highly associated with variation in the severity of RP1-D21-induced HR. We have previously shown that the two maize HCT homologs suppress the HR conferred by RP1-D21 in a heterologous system, very likely through physical interaction. Here, we show, similarly, that CCoAOMT2 suppresses the HR induced by either the full-length or by the N-terminal coiled-coil domain of RP1-D21 also likely via physical interaction and that the metabolic activity of CCoAOMT2 is unlikely to be necessary for its role in suppressing HR. We also demonstrate that CCoAOMT2, HCTs, and RP1 proteins can form in the same complexes. A model is derived to explain the roles of CCoAOMT and HCT in RP1-mediated defense resistance.
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maize homologs of hydroxycinnamoyltransferase a key enzyme in lignin biosynthesis bind the nucleotide binding leucine rich repeat RP1 proteins to modulate the defense response
Plant Physiology, 2015Co-Authors: Guanfeng Wang, Yijian He, Renee C Strauch, Bode A Olukolu, Dahlia Nielsen, Xu Li, Peter J BalintkurtiAbstract:In plants, most disease resistance genes encode nucleotide binding Leu-rich repeat (NLR) proteins that trigger a rapid localized cell death called a hypersensitive response (HR) upon pathogen recognition. The maize (Zea mays) NLR protein RP1-D21 derives from an intragenic recombination between two NLRs, RP1-D and RP1-dp2, and confers an autoactive HR in the absence of pathogen infection. From a previous quantitative trait loci and genome-wide association study, we identified a single-nucleotide polymorphism locus highly associated with variation in the severity of RP1-D21-induced HR. Two maize genes encoding hydroxycinnamoyltransferase (HCT; a key enzyme involved in lignin biosynthesis) homologs, termed HCT1806 and HCT4918, were adjacent to this single-nucleotide polymorphism. Here, we show that both HCT1806 and HCT4918 physically interact with and suppress the HR conferred by RP1-D21 but not other autoactive NLRs when transiently coexpressed in Nicotiana benthamiana. Other maize HCT homologs are unable to confer the same level of suppression on RP1-D21-induced HR. The metabolic activity of HCT1806 and HCT4918 is unlikely to be necessary for their role in suppressing HR. We show that the lignin pathway is activated by RP1-D21 at both the transcriptional and metabolic levels. We derive a model to explain the roles of HCT1806 and HCT4918 in RP1-mediated disease resistance.
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cytoplasmic and nuclear localizations are important for the hypersensitive response conferred by maize autoactive RP1 d21 protein
Molecular Plant-microbe Interactions, 2015Co-Authors: Guanfeng Wang, Peter J BalintkurtiAbstract:Disease resistance (R) genes have been isolated from many plant species. Most encode nucleotide binding leucine-rich repeat (NLR) proteins that trigger a rapid localized programmed cell death called the hypersensitive response (HR) upon pathogen recognition. Despite their structural similarities, different NLR are distributed in a range of subcellular locations, and analogous domains play diverse functional roles. The autoactive maize NLR gene RP1-D21 derives from an intragenic recombination between two NLR genes, RP1-D and RP1-dp2, and confers a HR independent of the presence of a pathogen. RP1-D21 and its N-terminal coiled coil (CC) domain (CCD21) confer autoactive HR when transiently expressed in Nicotiana benthamiana. RP1-D21 was predominantly localized in cytoplasm with a small amount in the nucleus, while CCD21 was localized in both nucleus and cytoplasm. Targeting of RP1-D21 or CCD21 predominantly to either the nucleus or the cytoplasm abolished HR-inducing activity. Coexpression of RP1-D21 or CCD2...
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characterization of temperature and light effects on the defense response phenotypes associated with the maize RP1 d21 autoactive resistance gene
BMC Plant Biology, 2013Co-Authors: Adisu Negeri, Guanfeng Wang, Larissa M Benavente, Cromwell M Kibiti, Vijay Chaikam, Guri Johal, Peter J BalintkurtiAbstract:RP1 is a complex locus of maize, which carries a set of genes controlling race-specific resistance to the common rust fungus, Puccinia sorghi. The resistance response includes the “Hypersensitive response” (HR), a rapid response triggered by a pathogen recognition event that includes localized cell death at the point of pathogen penetration and the induction of pathogenesis associated genes. The RP1-D21gene is an autoactive allelic variant at the RP1 locus, causing spontaneous activation of the HR response, in the absence of pathogenesis. Previously we have shown that the severity of the phenotype conferred by RP1-D21 is highly dependent on genetic background. In this study we show that the phenotype conferred by RP1-D21 is highly dependent on temperature, with lower temperatures favoring the expression of the HR lesion phenotype. This temperature effect was observed in all the 14 genetic backgrounds tested. Significant interactions between the temperature effects and genetic background were observed. When plants were grown at temperatures above 30°C, the spontaneous HR phenotype conferred by RP1-D21 was entirely suppressed. Furthermore, this phenotype could be restored or suppressed by alternately reducing and increasing the temperature appropriately. Light was also required for the expression of this phenotype. By examining the expression of genes associated with the defense response we showed that, at temperatures above 30°C, the RP1-D21 phenotype was suppressed at both the phenotypic and molecular level. We have shown that the lesion phenotype conferred by maize autoactive resistance gene RP1-D21 is temperature sensitive in a reversible manner, that the temperature-sensitivity phenotype interacts with genetic background and that the phenotype is light sensitive. This is the first detailed demonstration of this phenomenon in monocots and also the first demonstration of the interaction of this effect with genetic background. The use of temperature shifts to induce a massive and synchronous HR in plants carrying the RP1-D21 genes will be valuable in identifying components of the defense response pathway.
