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Gordon N Gill - One of the best experts on this subject based on the ideXlab platform.
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the LIM Domain only protein lmo4 is required for neural tube closure
Molecular and Cellular Neuroscience, 2005Co-Authors: Soo Kyung Lee, Samuel L. Pfaff, Linda W Jurata, Roberta B Nowak, Karen Lettieri, Daryn A Kenny, Gordon N GillAbstract:Nuclear LIM Domain-only proteins (LMOs), which consist of two closely spaced 50 amino acid Zn2+–finger protein interaction modules mediate interactions between several classes of transcription factors important for development. LMO2 is necessary for development of the entire hematopoietic system and overexpression of LMO1 or LMO2 results in human acute T cell leukemia. LMO4 is the most widely expressed LMO but its normal function is unknown. During development, LMO4 is expressed in dividing neuroepithelial cells within the ventricular zone along the entire rostrocaudal axis of the nervous system. In telencephalic and spinal cord regions of the CNS, LMO4 is highly expressed in ventral but is low in dorsal proliferating neuroepithelial cells. To understand the role of LMO4 during mouse development, we generated a homozygous null mutation in the gene. We found that LMO4 is required for proper closure of the anterior neural tube. In the absence of LMO4, elevation, bending, and proliferation of the ventral neural epithelium and consequent fusion of the prospective dorsal ends of the neural tube do not occur. LMO4 mutant mice die embryonically and exhibit exencephaly, which is associated with abnormal patterns of cell proliferation and with high levels of apoptotic cell death within the neuroepithelium. LMO4 is thus essential for normal patterns of proliferation and for survival of neural epithelial cells in the rostral neural tube. LMO4 is also expressed in Schwann cell progenitors after these contact neurites, a process mediated in part by neuregulin (Nrg).
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the nuclear LIM Domain interactor nli mediates homo and heterodimerization of LIM Domain transcription factors
Journal of Biological Chemistry, 1998Co-Authors: Linda W Jurata, Samuel L. Pfaff, Gordon N GillAbstract:Abstract LIM Domain-containing transcription factors are required for embryonic survival and for the determination of many cell types. The combinatorial expression of the LIM homeoDomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeoDomain protein combinations in the specification of neuronal identity. NLI is a widely expressed, dimeric protein that has been shown to specifically interact with the LIM Domains of LIM Domain-containing transcription factors. The present studies demonstrate that NLI mediates homo- and heteromeric complex formation between LIM Domain transcription factors, requiring both the N-terminal dimerization and C-terminal LIM interaction Domains of NLI. Although the interaction between most LIM homeoDomain proteins is dependent on NLI, a direct interaction between the LIM Domains of Lhx3 and the homeoDomains of Isl1 and Isl2 was also observed. This interaction was disrupted by NLI, demonstrating that the conformational state of Lhx3-Isl1/Isl2 complexes is modified by NLI. Evidence indicating that NLI facilitates long range enhancer-promoter interactions suggests that NLI-dependent LIM Domain transcription factor complexes are involved in communication between transcriptional control elements.
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functional analysis of the nuclear LIM Domain interactor nli
Molecular and Cellular Biology, 1997Co-Authors: Linda W Jurata, Gordon N GillAbstract:LIM homeoDomain and LIM-only (LMO) transcription factors contain two tandemly arranged Zn2+-binding LIM Domains capable of mediating protein-protein interactions. These factors have restricted patterns of expression, are found in invertebrates as well as vertebrates, and are required for cell type specification in a variety of developing tissues. A recently identified, widely expressed protein, NLI, binds with high affinity to the LIM Domains of LIM homeoDomain and LMO proteins in vitro and in vivo. In this study, a 38-amino-acid fragment of NLI was found to be sufficient for the association of NLI with nuclear LIM Domains. In addition, NLI was shown to form high affinity homodimers through the amino-terminal 200 amino acids, but dimerization of NLI was not required for association with the LIM homeoDomain protein Lmxl. Chemical cross-linking analysis revealed higher-order complexes containing multiple NLI molecules bound to Lmx1, indicating that dimerization of NLI does not interfere with LIM Domain interactions. Additionally, NLI formed complexes with Lmx1 on the rat insulin I promoter and inhibited the LIM Domain-dependent synergistic transcriptional activation by Lmx1 and the basic helix-loop-helix protein E47 from the rat insulin I minienhancer. These studies indicate that NLI contains at least two functionally independent Domains and may serve as a negative regulator of synergistic transcriptional responses which require direct interaction via LIM Domains. Thus, NLI may regulate the transcriptional activity of LIM homeoDomain proteins by determining specific partner interactions.
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mitogenic signaling by ret ptc2 requires association with enigma via a LIM Domain
Journal of Biological Chemistry, 1996Co-Authors: Kyle Durick, Gordon N Gill, Susan S TaylorAbstract:The ret/ptc2 papillary thyroid cancer oncogene, an oncogenic form of the c-Ret receptor tyrosine kinase, is the product of a somatic crossover event fusing the dimerization Domain of the type Ialpha regulatory subunit of cyclic AMP-dependent protein kinase (RI) with the tyrosine kinase Domain of c-Ret. Mitogenic activity of Ret/ptc2 required dimerization via the N terminus of RI and a tyrosine residue located C-terminal to the kinase core of Ret, Tyr-586 (Durick, K., Yao, V. J., Borrello, M. G., Bongarzone, I., Pierotti, M. A. and Taylor, S. S. (1995) J. Biol. Chem. 270, 24642-24645). Using the yeast two-hybrid system, Ret/ptc2 binding proteins were identified, and the sites of interaction with Ret/ptc2 were mapped. The SH2 Domains of phospholipase Cgamma and Grb10 were both identified, and binding depended on phosphorylation of Tyr-539 and Tyr-429, respectively. These interactions, however, were not required for mitogenic signaling. The second of the three LIM Domains in Enigma (Wu, R. Y., and Gill, G. N. (1994) J. Biol. Chem. 269, 25085-25090) was also identified as a Ret/ptc2 binding Domain. Enigma, a 455-residue protein, was discovered based on its interaction with the insulin receptor through the C-terminal LIM Domain. Although the association with Enigma required Tyr-586 of Ret/ptc2, the interaction was phosphorylation-independent. In contrast to the SH2 interactions, disruption of the interaction with Enigma abolished Ret/ptc2 mitogenic signaling, suggesting that LIM Domain recognition of an unphosphorylated tyrosine-based motif is required for Ret signal transduction.
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LIM Domain recognition of a tyrosine containing tight turn
Journal of Biological Chemistry, 1994Co-Authors: Gordon N GillAbstract:Endocytosis of cell surface receptors requires sequence "codes" consisting of tight turn structures with an essential Tyr or Phe residue. To determine mechanisms through which cells recognize this information, we utilized exon 16 of the human insulin receptor in the two-hybrid system to isolate a novel 455-amino acid cytoplasmic protein that contains two LIM Domains within its carboxyl terminus. Mutational analyses indicate that one of the Cys-rich Zn2+ binding LIM Domains specifically recognizes active but not inactive endocytic codes contained in exon 16. These findings suggest that LIM Domain structures in proteins provide molecular recognition of Tyr-containing tight turn structures.
Cristine Allmer - One of the best experts on this subject based on the ideXlab platform.
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LIM Domain only 2 protein expression lmo2 germline genetic variation and overall survival in diffuse large b cell lymphoma in the pre rituximab era
Leukemia & Lymphoma, 2012Co-Authors: James R Cerhan, Mohammad A Vasef, Thomas Matthew Habermann, Matthew J Maurer, Charles F Lynch, Yasodha Natkunam, Lindsay M Morton, Yan W. Asmann, Wendy Cozen, Cristine AllmerAbstract:AbstractBoth LMO2 (LIM Domain only 2) mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival. However, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (hazard ratio [HR] = 0.55; 95% confidence interval [CI] 0.31–0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p < 0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p = 0.02). Compared to a model with clinical factors only (c-statistic = 0.676), adding the four SNPs (c-statistic = 0.751) or LMO2 IHC (c-statistic = 0.691) increased the predictive ability of the model, while inclusion of all three factors ...
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LIM Domain only 2 protein expression lmo2 germline genetic variation and overall survival in diffuse large b cell lymphoma in the pre rituximab era
Leukemia & Lymphoma, 2012Co-Authors: James R Cerhan, Mohammad A Vasef, Thomas Matthew Habermann, Matthew J Maurer, Charles F Lynch, Yasodha Natkunam, Lindsay M Morton, Yan W. Asmann, Wendy Cozen, Cristine AllmerAbstract:Both LMO2 (LIM Domain only 2) mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival. However, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (hazard ratio [HR] = 0.55; 95% confidence interval [CI] 0.31-0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p < 0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p = 0.02). Compared to a model with clinical factors only (c-statistic = 0.676), adding the four SNPs (c-statistic = 0.751) or LMO2 IHC (c-statistic = 0.691) increased the predictive ability of the model, while inclusion of all three factors (c-statistic = 0.754) did not meaningfully add predictive ability above a model with clinical factors and the four SNPs. In conclusion, germline genetic variation in LMO2 was associated with DLBCL prognosis and provided slightly stronger predictive ability relative to LMO2 IHC status.
Linda W Jurata - One of the best experts on this subject based on the ideXlab platform.
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the LIM Domain only protein lmo4 is required for neural tube closure
Molecular and Cellular Neuroscience, 2005Co-Authors: Soo Kyung Lee, Samuel L. Pfaff, Linda W Jurata, Roberta B Nowak, Karen Lettieri, Daryn A Kenny, Gordon N GillAbstract:Nuclear LIM Domain-only proteins (LMOs), which consist of two closely spaced 50 amino acid Zn2+–finger protein interaction modules mediate interactions between several classes of transcription factors important for development. LMO2 is necessary for development of the entire hematopoietic system and overexpression of LMO1 or LMO2 results in human acute T cell leukemia. LMO4 is the most widely expressed LMO but its normal function is unknown. During development, LMO4 is expressed in dividing neuroepithelial cells within the ventricular zone along the entire rostrocaudal axis of the nervous system. In telencephalic and spinal cord regions of the CNS, LMO4 is highly expressed in ventral but is low in dorsal proliferating neuroepithelial cells. To understand the role of LMO4 during mouse development, we generated a homozygous null mutation in the gene. We found that LMO4 is required for proper closure of the anterior neural tube. In the absence of LMO4, elevation, bending, and proliferation of the ventral neural epithelium and consequent fusion of the prospective dorsal ends of the neural tube do not occur. LMO4 mutant mice die embryonically and exhibit exencephaly, which is associated with abnormal patterns of cell proliferation and with high levels of apoptotic cell death within the neuroepithelium. LMO4 is thus essential for normal patterns of proliferation and for survival of neural epithelial cells in the rostral neural tube. LMO4 is also expressed in Schwann cell progenitors after these contact neurites, a process mediated in part by neuregulin (Nrg).
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the nuclear LIM Domain interactor nli mediates homo and heterodimerization of LIM Domain transcription factors
Journal of Biological Chemistry, 1998Co-Authors: Linda W Jurata, Samuel L. Pfaff, Gordon N GillAbstract:Abstract LIM Domain-containing transcription factors are required for embryonic survival and for the determination of many cell types. The combinatorial expression of the LIM homeoDomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeoDomain protein combinations in the specification of neuronal identity. NLI is a widely expressed, dimeric protein that has been shown to specifically interact with the LIM Domains of LIM Domain-containing transcription factors. The present studies demonstrate that NLI mediates homo- and heteromeric complex formation between LIM Domain transcription factors, requiring both the N-terminal dimerization and C-terminal LIM interaction Domains of NLI. Although the interaction between most LIM homeoDomain proteins is dependent on NLI, a direct interaction between the LIM Domains of Lhx3 and the homeoDomains of Isl1 and Isl2 was also observed. This interaction was disrupted by NLI, demonstrating that the conformational state of Lhx3-Isl1/Isl2 complexes is modified by NLI. Evidence indicating that NLI facilitates long range enhancer-promoter interactions suggests that NLI-dependent LIM Domain transcription factor complexes are involved in communication between transcriptional control elements.
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functional analysis of the nuclear LIM Domain interactor nli
Molecular and Cellular Biology, 1997Co-Authors: Linda W Jurata, Gordon N GillAbstract:LIM homeoDomain and LIM-only (LMO) transcription factors contain two tandemly arranged Zn2+-binding LIM Domains capable of mediating protein-protein interactions. These factors have restricted patterns of expression, are found in invertebrates as well as vertebrates, and are required for cell type specification in a variety of developing tissues. A recently identified, widely expressed protein, NLI, binds with high affinity to the LIM Domains of LIM homeoDomain and LMO proteins in vitro and in vivo. In this study, a 38-amino-acid fragment of NLI was found to be sufficient for the association of NLI with nuclear LIM Domains. In addition, NLI was shown to form high affinity homodimers through the amino-terminal 200 amino acids, but dimerization of NLI was not required for association with the LIM homeoDomain protein Lmxl. Chemical cross-linking analysis revealed higher-order complexes containing multiple NLI molecules bound to Lmx1, indicating that dimerization of NLI does not interfere with LIM Domain interactions. Additionally, NLI formed complexes with Lmx1 on the rat insulin I promoter and inhibited the LIM Domain-dependent synergistic transcriptional activation by Lmx1 and the basic helix-loop-helix protein E47 from the rat insulin I minienhancer. These studies indicate that NLI contains at least two functionally independent Domains and may serve as a negative regulator of synergistic transcriptional responses which require direct interaction via LIM Domains. Thus, NLI may regulate the transcriptional activity of LIM homeoDomain proteins by determining specific partner interactions.
Ralf Weiskirchen - One of the best experts on this subject based on the ideXlab platform.
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the expression of csrp2 encoding the LIM Domain protein crp2 is mediated by tgf β in smooth muscle and hepatic stellate cells
Biochemical and Biophysical Research Communications, 2006Co-Authors: J Herrmann, Axel M Gressner, Erawan Borkhamkamphorst, U Haas, Eddy Van De Leur, Mario F Fraga, Manel Esteller, Ralf WeiskirchenAbstract:Abstract Transforming growth factor-β (TGF-β) is a cytokine implicated in differentiation of smooth muscle cells and other mesenchymal-derived cells. During hepatic fibrogenesis, TGF-β has a pivotal role in the initiation, promotion, and progression of transdifferentiation of hepatic stellate cells into myofibroblasts that play a central role in the synthesis of extracellular matrix components. Both, smooth muscle and activated hepatic stellate cells, express smooth muscle α-actin, the calponin-related protein SM22α, and CSRP2 encoding the cysteine- and glycine-rich LIM Domain protein 2 (CRP2). The aim of the present study was to determine whether the expression of CSRP2 is influenced by TGF-β. Stimulation as well as sequestering experiments demonstrated that TGF-β markedly influences CSRP2 gene activity. Inhibition experiments using the ALK5 inhibitor SB-431542 further reveal that the transcriptional stimulation of the CSRP2 gene is mediated via the ALK5/Smad2/Smad3 signalling pathway. By use of bisulfite genomic analysis of CpG islands within the 5′ regulatory regions we could exclude methylation-associated silencing, previously found to be responsible for the transcriptional inactivity of CSRP2 in a variety of human cancer cells and in a multistage carcinogenesis model, as a cause for CSRP2 inactivity in hepatocytes or fully transdifferentiated myofibroblasts.
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the crp mlp tlp family of LIM Domain proteins acting by connecting
BioEssays, 2003Co-Authors: Ralf Weiskirchen, Kalle GuntherAbstract:In vertebrates, members of the cysteine-rich protein (CRP) family are characterized by the presence of two LIM Domains linked to short glycine-rich repeats. These proteins mediate protein-protein interactions and are of fundamental importance for cell differentiation, cytoskeletal remodeling, and transcriptional regulation. To date, a vast amount of information about vertebrate CRPs has become available, including their biological functions, interacting partners, and three-dimensional structures. Compatible with a molecular adapter role, structural data reveal that the LIM Domains within these proteins represent completely independent folded units bridged by flexible linker regions. The physiological roles for individual CRPs was determined by targeted gene disruption analysis and by identification of common and specific binding partners by means of yeast and mammalian two-hybrid screens. Several CRP-like LIM Domain proteins with close structural and sequence similarity were identified in arthropods, protozoas and plants, supporting the notion that this subset of LIM Domain proteins has been highly conserved over the span of evolution thereby emphasizing the importance of their function.
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LIM Domain protein cysteine and glycine rich protein 2 crp2 is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated stat1
Biochemical Journal, 2001Co-Authors: Ralf Weiskirchen, Markus Moser, Sabine Weiskirchen, Martin Erdel, Sandra Dahmen, Reinhard Buettner, Axel M GressnerAbstract:Activation of hepatic stellate cells is considered to be the main step in the development of liver fibrosis, which is characterized by the transition of quiescent vitamin-A-rich cells to proliferative, fibrogenic and contractile myofibroblasts. The identification of regulatory genes during early cell activation and transdifferentiation is essential to extend our knowledge of hepatic fibrogenesis. In liver, the gene CSRP2 is exclusively expressed by stellate cells, whereas no transcripts are detectable in hepatocytes, sinusoidal endothelial cells or Kupffer cells. The early activation of stellate cells induced by platelet-derived growth factor is accompanied by an enhanced expression of CSRP2. During later stages of transdifferentiation, the expression of CSRP2 in these cells is suppressed in vitro and in vivo. The CSRP2-encoded cysteine- and glycine-rich double-LIM-Domain protein (CRP)2 is proposed to function as a molecular adapter, arranging two or more as yet unidentified protein constituents into a macromolecular complex. To identify these proteins and assign a cellular function to CRP2, a human cDNA library was screened with full-length CRP2 as bait in a yeast two-hybrid screen. The protein inhibitor of activated STAT1 ('PIAS1') was shown to associate selectively with the C-terminal LIM Domain of CRP2. Physical interaction of both proteins in the cellular environment was confirmed by co-localization experiments with confocal laser scanning microscopy and co-immunoprecipitation analysis. These results establish CRP2 as a potential new factor in the JAK/STAT-signalling pathway and suggest that the suppression of CSRP2 might be a prerequisite for the myofibroblastic transition of hepatic stellate cells.
James R Cerhan - One of the best experts on this subject based on the ideXlab platform.
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LIM Domain only 2 protein expression lmo2 germline genetic variation and overall survival in diffuse large b cell lymphoma in the pre rituximab era
Leukemia & Lymphoma, 2012Co-Authors: James R Cerhan, Mohammad A Vasef, Thomas Matthew Habermann, Matthew J Maurer, Charles F Lynch, Yasodha Natkunam, Lindsay M Morton, Yan W. Asmann, Wendy Cozen, Cristine AllmerAbstract:AbstractBoth LMO2 (LIM Domain only 2) mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival. However, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (hazard ratio [HR] = 0.55; 95% confidence interval [CI] 0.31–0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p < 0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p = 0.02). Compared to a model with clinical factors only (c-statistic = 0.676), adding the four SNPs (c-statistic = 0.751) or LMO2 IHC (c-statistic = 0.691) increased the predictive ability of the model, while inclusion of all three factors ...
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LIM Domain only 2 protein expression lmo2 germline genetic variation and overall survival in diffuse large b cell lymphoma in the pre rituximab era
Leukemia & Lymphoma, 2012Co-Authors: James R Cerhan, Mohammad A Vasef, Thomas Matthew Habermann, Matthew J Maurer, Charles F Lynch, Yasodha Natkunam, Lindsay M Morton, Yan W. Asmann, Wendy Cozen, Cristine AllmerAbstract:Both LMO2 (LIM Domain only 2) mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival. However, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (hazard ratio [HR] = 0.55; 95% confidence interval [CI] 0.31-0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p < 0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p = 0.02). Compared to a model with clinical factors only (c-statistic = 0.676), adding the four SNPs (c-statistic = 0.751) or LMO2 IHC (c-statistic = 0.691) increased the predictive ability of the model, while inclusion of all three factors (c-statistic = 0.754) did not meaningfully add predictive ability above a model with clinical factors and the four SNPs. In conclusion, germline genetic variation in LMO2 was associated with DLBCL prognosis and provided slightly stronger predictive ability relative to LMO2 IHC status.