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Terence H. Rabbitts - One of the best experts on this subject based on the ideXlab platform.
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the lmo2 t Cell Oncogene is activated via chromosomal translocations or retroviral insertion during gene therapy but has no mandatory role in normal t Cell development
Molecular and Cellular Biology, 2003Co-Authors: Matthew P Mccormack, Lesley F. Drynan, Richard Pannell, Terence H. RabbittsAbstract:The LMO2 gene encodes a LIM-only protein and is a target of chromosomal translocations in human T-Cell leukemia. Recently, two X-SCID patients treated by gene therapy to rescue T-Cell lymphopoiesis developed T-Cell leukemias with retroviral insertion into the LMO2 gene causing clonal T-Cell proliferation. In view of the specificity of LMO2 in T-Cell tumorigenesis, we investigated a possible role for Lmo2 in T-lymphopoiesis, using conditional knockout of mouse Lmo2 with loxP-flanked Lmo2 and Cre recombinase alleles driven by the promoters of the lymphoid-specific genes Rag1, CD19, and Lck. While efficient deletion of Lmo2 was observed, even in the earliest detectable lymphoid Cell progenitors of the bone marrow, there was no disturbance of lymphopoiesis in either T- or B-Cell lineages, and in contrast to Lmo2 transgenic mice, there were normal distributions of CD4− CD8− thymocytes. We conclude that there is no mandatory role for LMO2 in lymphoid development, implying that its specific role in T-Cell tumorigenesis results from a reprogramming of gene expression after enforced expression in T-Cell precursors.
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The T Cell Oncogene Tal2 is necessary for normal development of the mouse brain.
Developmental biology, 2000Co-Authors: Katharina Bucher, Richard Pannell, Michael V. Sofroniew, Helen Impey, Andrew J.h. Smith, Eduardo Miguel Torres, Stephen B. Dunnett, Ying Jin, Richard Baer, Terence H. RabbittsAbstract:Transcription factors are commonly involved in leukemia by activation through chromosomal translocations and normally function in Cell type(s) that differ from that of the tumor. TAL2 is a member of a basic helix–loop–helix gene family specifically involved in T Cell leukemogenesis. Null mutations of Tal2 have been made in mice to determine its function during development. Tal2 null mutant mice show no obvious defects of hematopoiesis. During embryogenesis, Tal2 expression is restricted to the developing midbrain, dorsal diencephalon, and rostroventral diencephalic/telencephalic boundary, partly along presumptive developing fiber tracts. The null mutant mice are viable at birth but growth become progressively retarded and they do not survive to reproductive age. Tal2-deficient mice show a distinct dysgenesis of the midbrain tectum. Due to loss of superficial gray and optical layers, the superior colliculus is reduced in size and the inferior colliculus is abnormally rounded and protruding. Death is most likely due to progressive hydrocephalus which appears to be caused by obstruction of the foramen of Monro (the connection between the ventricles of the forebrain). Thus, in addition to its oncogenicity when ectopically expressed, Tal2 normally plays a pivotal role in brain development and without this gene, mice cannot survive to maturity.
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A Drosophila melanogaster homologue of the T-Cell Oncogene HOX11 localises to a cluster of homeobox genes.
Gene, 1994Co-Authors: Terence Neil Dear, Terence H. RabbittsAbstract:The human homeobox gene HOX11 has been identified at the site of a chromosomal translocation in a subset of T-Cell acute leukaemias. In the mouse genome, the hox11 family consists of at least three related genes, each of which possesses a highly conserved homeobox. To assist in elucidating the roles of this gene, a homologue was studied from Drosophila melanogaster. This gene, 311, shares similar identity to all three murine family members and contains the threonine residue in helix 3 of the homeodomain characteristic of the Hox11 family. It maps to a cluster of NK-homeobox genes which function in muscle development. Gene 311 exhibits a similar temporal pattern of expression to the NK genes in this cluster. Therefore, 311 may constitute part of a homeobox cluster in which the genes are both co-ordinately regulated and functionally related.
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HOX11, a homeobox-containing T-Cell Oncogene on human chromosome 10q24.
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Martin A. Kennedy, T. Boehm, Rogelio González-sarmiento, U R Kees, F Lampert, N Dear, Terence H. RabbittsAbstract:Abstract A common chromosomal abnormality in childhood T-Cell acute leukemia is a translocation, t(10;14) (q24;q11), that together with the variant t(7;10)(q35;q24) is present in up to 7% of this tumor type. The gene adjacent to the 10q24 region is transcriptionally activated after translocation to either TCRD (14q11) or TCRB (7q35). It encodes a homeobox gene closely related to the developmentally regulated homeotic genes of flies and mammals. The coding capacity of this activated gene, designated HOX11, is undisturbed in a T-Cell line carrying the translocation t(7;10)(q35;q24). Therefore, the HOX11 homeobox gene seems to be involved in T-Cell tumorigenesis.
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Developmentally regulated and tissue specific expression of mRNAs encoding the two alternative forms of the LIM domain Oncogene rhombotin: evidence for thymus expression.
Oncogene, 1991Co-Authors: T. Boehm, M A Surani, Maria Grazia Spillantini, Michael V. Sofroniew, Terence H. RabbittsAbstract:The T-Cell Oncogene rhombotin was first identified as a gene near a chromosomal translocation breakpoint in a human T-Cell tumour and represents the first example of an Oncogene carrying the duplicated cysteine-rich regions (CRR or LIM domains). Transgenic expression of a reporter gene under the control of one of the rhombotin gene promoters subsequently showed high levels of expression in the developing brain. These disparate sites of transcriptional activity suggested that the gene may have been activated de novo specifically in the T Cell tumour via the translocation. Here, we assess this possibility by analysing rhombotin gene expression in mouse development by in situ hybridization of whole embryos, Northern filter hybridization, and a sensitive semiquantitative PCR method. The results show that the central nervous system is the major site of rhombotin mRNA production. Low level expression does, however, occur in other tissues including thymus. Furthermore, both promoters are active and differentially regulated during mouse embryogenesis in both brain and thymus. In subregions of the adult brain, different levels of rhombotin activity can be observed, with evidence for regional variation in promoter usage. A detailed analysis of mouse and human T-Cell differentiation suggests that fluctuating promoter activities are related to a general T-Cell differentiation process rather than to the differentiation of functionally distinct subsets of T-Cells. These data suggest that the transforming activity of rhombotin in the T-Cell with the chromosomal translocation was not due to de novo transcriptional activation, but rather to a quantitative or qualitative change in expression levels of this CRR-containing Oncogene after chromosomal translocation.
Wanjin Hong - One of the best experts on this subject based on the ideXlab platform.
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retinoblastoma binding protein 2 rbp2 potentiates nuclear hormone receptor mediated transcription
Journal of Biological Chemistry, 2001Co-Authors: Siew Wee Chan, Wanjin HongAbstract:Abstract Retinoblastoma-binding protein 2 (Rbp2) was originally identified as a retinoblastoma protein (RB) pocket domain-binding protein. Although Rbp2 has been shown to interact with RB, p107, TATA-binding protein, and T-Cell Oncogene rhombotin-2, the physiological function of Rbp2 remains unclear. Here we demonstrate that Rbp2 not only binds to nuclear receptors (NRs) but also enhances the transcription mediated by them. Rbp2 interacts with the DNA-binding domains of NRs and potentiates NR-mediated transcription in an AF-2-dependent manner. Both the N-terminal and C-terminal domains of Rbp2 are critical for the transactivation activity of Rbp2 on NRs. The C terminus is the NR-interacting region. In addition, RB functions in maximizing the effect of Rbp2 on the transcription by NRs. These results suggest that Rbp2 is a coregulator of NRs and define a potential role for Rbp2 in NR-mediated transcription.
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Retinoblastoma-binding Protein 2 (Rbp2) Potentiates Nuclear Hormone Receptor-mediated Transcription *
The Journal of biological chemistry, 2001Co-Authors: Siew Wee Chan, Wanjin HongAbstract:Retinoblastoma-binding protein 2 (Rbp2) was originally identified as a retinoblastoma protein (RB) pocket domain-binding protein. Although Rbp2 has been shown to interact with RB, p107, TATA-binding protein, and T-Cell Oncogene rhombotin-2, the physiological function of Rbp2 remains unclear. Here we demonstrate that Rbp2 not only binds to nuclear receptors (NRs) but also enhances the transcription mediated by them. Rbp2 interacts with the DNA-binding domains of NRs and potentiates NR-mediated transcription in an AF-2-dependent manner. Both the N-terminal and C-terminal domains of Rbp2 are critical for the transactivation activity of Rbp2 on NRs. The C terminus is the NR-interacting region. In addition, RB functions in maximizing the effect of Rbp2 on the transcription by NRs. These results suggest that Rbp2 is a coregulator of NRs and define a potential role for Rbp2 in NR-mediated transcription.
Siew Wee Chan - One of the best experts on this subject based on the ideXlab platform.
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retinoblastoma binding protein 2 rbp2 potentiates nuclear hormone receptor mediated transcription
Journal of Biological Chemistry, 2001Co-Authors: Siew Wee Chan, Wanjin HongAbstract:Abstract Retinoblastoma-binding protein 2 (Rbp2) was originally identified as a retinoblastoma protein (RB) pocket domain-binding protein. Although Rbp2 has been shown to interact with RB, p107, TATA-binding protein, and T-Cell Oncogene rhombotin-2, the physiological function of Rbp2 remains unclear. Here we demonstrate that Rbp2 not only binds to nuclear receptors (NRs) but also enhances the transcription mediated by them. Rbp2 interacts with the DNA-binding domains of NRs and potentiates NR-mediated transcription in an AF-2-dependent manner. Both the N-terminal and C-terminal domains of Rbp2 are critical for the transactivation activity of Rbp2 on NRs. The C terminus is the NR-interacting region. In addition, RB functions in maximizing the effect of Rbp2 on the transcription by NRs. These results suggest that Rbp2 is a coregulator of NRs and define a potential role for Rbp2 in NR-mediated transcription.
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Retinoblastoma-binding Protein 2 (Rbp2) Potentiates Nuclear Hormone Receptor-mediated Transcription *
The Journal of biological chemistry, 2001Co-Authors: Siew Wee Chan, Wanjin HongAbstract:Retinoblastoma-binding protein 2 (Rbp2) was originally identified as a retinoblastoma protein (RB) pocket domain-binding protein. Although Rbp2 has been shown to interact with RB, p107, TATA-binding protein, and T-Cell Oncogene rhombotin-2, the physiological function of Rbp2 remains unclear. Here we demonstrate that Rbp2 not only binds to nuclear receptors (NRs) but also enhances the transcription mediated by them. Rbp2 interacts with the DNA-binding domains of NRs and potentiates NR-mediated transcription in an AF-2-dependent manner. Both the N-terminal and C-terminal domains of Rbp2 are critical for the transactivation activity of Rbp2 on NRs. The C terminus is the NR-interacting region. In addition, RB functions in maximizing the effect of Rbp2 on the transcription by NRs. These results suggest that Rbp2 is a coregulator of NRs and define a potential role for Rbp2 in NR-mediated transcription.
Th Rabbitts - One of the best experts on this subject based on the ideXlab platform.
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LMO2 and IL2RG synergize in thymocytes to mimic the evolution of SCID-X1 gene therapy-associated T-Cell leukaemia
'Springer Science and Business Media LLC', 2016Co-Authors: Ruggero K, Al-assar O, Js Chambers, Codrington R, Brend T, Th RabbittsAbstract:The SCID-X1 disease occurs in males that lack a functional X-linked gene encoding the interleukin 2 receptor subunit gamma (IL2RG) and thus are immuno-deficient (reviewed in Rochman et al.). Gene therapy has been a success in curing SCID-X1 in patients receiving autologous CD34+-bone marrow Cells infected with retroviruses expressing IL2RG. This treatment protocol has, however, produced adverse T-Cell effects where clonal T-Cell leukaemias arose, and four have insertional mutagenesis of the T-Cell Oncogene LMO2. LMO2 is a T-Cell Oncogene first discovered via chromosomal translocations in T-Cell acute leukaemia (T-ALL) (reviewed in Chambers and Rabbitts). It is unclear if the T-Cell neoplasias in the SCID-X1 patients are simply due to insertional activation of the LMO2 gene or reflect synergy between LMO2 and IL2RG. Further, the recurrent involvement of LMO2 in SCID-X1 leukaemias is puzzling as other T-Cell Oncogenes (for example, TAL1/SCL, HOX11 and LYL1) might equally have been targets. This suggests that specific properties of LMO2 per se are required in these adverse events. The oncogenic potential of IL2RG itself also remains controversial. Although it causes T-Cell lymphomas in mice transplanted with virally transduced haematopoetic stem Cells, other studies have indicated that IL2RG is not an Oncogene. Here we provide evidence that synergy is required between LMO2 and IL2RG proteins specifically in the T-Cell lineage to elicit neoplasias and that additional mutations are required such as Notch1 mutations like those in human T-ALL
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activation of the t Cell Oncogene lmo2 after gene therapy for x linked severe combined immunodeficiency
The New England Journal of Medicine, 2004Co-Authors: Matthew P Mccormack, Th RabbittsAbstract:Gene therapy, in which a retrovirus was used to carry the relevant gene (IL2Rγc) into a patient's hematopoietic stem Cells, was used to treat 10 boys with X-linked severe combined immunodeficiency (SCID). A syndrome resembling T-Cell leukemia developed in two of the boys. In both boys — and a third in whom leukemia has not developed — the retrovirus integrated into the same genomic site, the locus of LMO2, which is involved in childhood lymphocytic leukemia. This article reviews the molecular biology of these events and discusses their implications for the future of gene therapy.
Rakesh Goorha - One of the best experts on this subject based on the ideXlab platform.
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T-Cell Oncogene rhombotin-2 interacts with retinoblastoma-binding protein 2
Oncogene, 1997Co-Authors: Shifeng Mao, Geoffrey Neale, Rakesh GoorhaAbstract:The LIM domain protein rhombotin-2 (RBTN-2/TTG-2/Lmo2) has distinct functions in erythropoiesis and in T-Cell leukemogenesis. Additional functions for RBTN2 are indicated by its expression in non-hematopoietic tissues. These diverse functions of RBTN2 are presumed to be accomplished through physical interaction with different protein partners that bind the LIM domains of RBTN2. To identify these proteins which may modulate the activity of RBTN2, a human cDNA library was screened using the yeast two-hybrid assay. Using the RBTN2 LIM domain region as `bait', the retinoblastoma-binding protein 2 (RBP2) was identified as a partner for RBTN2. The interaction between RBTN2 and RBP2 was confirmed using in vitro binding assays, and by co-immunoprecipitation of the two proteins. Deletion analysis showed the second LIM domain of RBTN2 was necessary and sufficient for binding to the last 69 amino acids of RBP2. The interaction between RBTN2 and RBP2 had a functional consequence: the combination of RBP2 and RBTN2 gave higher transcription in vitro, than RBTN2 alone. The interaction with RBP2 suggests two additional functions for RBTN2: (i) RBTN2 may directly affect the activity of RBP2, and/or (ii) RBTN2 may indirectly modulate the functions of the retinoblastoma protein by binding to RBP2.
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T-Cell Proto-Oncogene Rhombotin-2 Is a Complex Transcription Regulator Containing Multiple Activation and Repression Domains *
The Journal of biological chemistry, 1997Co-Authors: Shifeng Mao, Geoffrey Neale, Rakesh GoorhaAbstract:The LIM domain protein rhombotin-2 (RBTN-2/TTG-2/LMO2) is involved in many processes, including leukemogenesis and erythropoiesis. It is thought that the principle role of RBTN-2 in these processes is to regulate transcription. To examine the potential for RBTN-2 to modulate transcription, we constructed RBTN-2/GAL4 DNA-binding domain fusion proteins and measured their ability to activate transcription of a reporter gene construct. From these studies we identified a transcription activation domain within the NH2 terminus of RBTN-2. This activation domain was further localized within a proline-rich 19-amino acid region. A second activation domain of 11 amino acids was also identified. This domain was located within the COOH terminus of RBTN-2, and functioned in mammalian Cells but not in yeast. Furthermore, the two LIM domains of RBTN-2 were shown to function as transcription repression domains. Each individual LIM domain acted as an independent transcription repression domain on a heterologous activation domain. However, in context of full-length RBTN-2, the LIM domains selectively repressed the NH2-terminal activation domain, but had no effect on the COOH-terminal domain. Overall, these results demonstrate that the T-Cell Oncogene RBTN-2 is a complex transcription factor possessing multiple transcription regulatory modules, including two activation domains and two repression domains.