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T H Rabbitts

Publications and source records attributed to T H Rabbitts.

At least 37 records · Page 2Linked to original sources
PubMed1999

Genomic structure, tissue expression and chromosomal location of the LIM-only gene, SLIM1.

Human SLIM1 is a recently described gene of the LIM-only class encoding four and a half tandemly repeated LIM domains. LIM domains are double zinc finger structures which provide an interface for protein/protein interactions and are conserved in a variety of nuclear and cytoplasmic factors important in cell fate determination and cellular regulation. Here we report the structural organization, expression pattern and chromosomal localization of the human SLIM1 gene. SLIM1 was found to contain at least five exons with all four introns disrupting the coding region at a similar position relative to the respective complete LIM domains. Northern blot analysis confirmed strikingly high expression of SLIM1 in skeletal muscle and heart, with much lower expression observed in several other tissues including colon, small intestine and prostate. The SLIM1 gene was assigned to human chromosome Xq26 using fluorescence in situ hybridization.

Chromosome Mapping↗
PubMed1999

The effect of chromosomal translocations in acute leukemias: the LMO2 paradigm in transcription and development.

Two general features have emerged about genes that are activated after chromosomal translocations in acute forms of cancer. The protein products of these genes are transcription regulators and are involved in developmental processes, and it seems that the subversion of these normal functions accounts for their role in tumorigenesis. The features of the LMO family of genes, which encode LIM-domain proteins involved in T-cell acute leukemia through chromosomal translocations, typify these abnormal functions in tumorigenesis. For example, the LMO2 protein is involved in the formation of multimeric DNA-binding complexes, which may vary in composition at different stages of hematopoiesis and function to control differentiation of specific lineages. In T cells, enforced expression of Lmo2 causes aberrant protein complex formation that primarily seems to hinder the T-cell differentiation program. These observations underscore the conclusion that protein-protein interaction (in this case, through the LIM domain) is a key determinant in tumorigenesis. Furthermore, the study of chromosomal translocations as naturally occurring mutations has been informative about mechanisms in hematopoiesis as well as in tumor etiology.

Acute Disease↗
PubMed1999

Perspective: chromosomal translocations can affect genes controlling gene expression and differentiation--why are these functions targeted?

Chromosomal translocations are important aetiological factors in many human cancers. These aberrant chromosomes cause enforced expression of oncogenes located near the breakpoints or results in tumour-specific fusion proteins. Among the characteristics which influence the tumourigenic effect, it is observed that the genes at translocation junctions are often transcription factors and often normally involved in developmental processes. Furthermore, protein-protein interactions are key elements in the mechanism by which the translocation gene products exert their pathogenic effects. In this review some of these salient features are discussed and generalizations are suggested which may be applicable to the influence of chromosomal translocations on acute forms of cancer.

Cell Transformation, Neoplastic↗
PubMed1999

Characterization of the Lmo4 gene encoding a LIM-only protein: genomic organization and comparative chromosomal mapping.

LIM-only (LMO) proteins are transcription regulators that function by mediating protein-protein interaction and include the T cell oncogenes encoding LMO1 and LMO2. The oncogenic functions of LMO1 and LMO2 are thought to be mediated by interaction with LDB1 since they form a multimeric protein complex(es). A new member of the Lmo family, Lmo4, has also recently been identified via its interaction with Ldb1. Sequence analysis of the mouse Lmo4 gene shows that it spans about 18 kb and consists of at least six exons, including two alternatively spliced 5' exons. Unlike Lmo1, the two 5' exons of Lmo4 do not encode protein. Comparison of the Lmo4 gene structure with the other LMO family members shows the exon structure of Lmo4 differs in the position of exon junctions encoding the second LIM domain and in a novel exon-intron junction at the penultimate codon of the gene. Lmo4 is thus the least conserved known member of the LIM-only family in both nucleotide sequence and exon structure. Physical mapping of the Lmo4/LMO4 genes has shown mouse Lmo4 is located on Chromosome (Chr) 3 and human LMO4 on Chr 1p22.3. This chromosome location is of interest as it occurs in a region that is deleted in a number of human cancers, indicating a possible role of LMO4 in tumorigenesis, like its relatives LMO1 and LMO2.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The LMO1 and LDB1 proteins interact in human T cell acute leukaemia with the chromosomal translocation t(11;14)(p15;q11).

The ectopic expression of LMO1 or LMO2 in T cell acute leukaemias resulting from chromosomal translocations t(11;14)(p15;qll) or t(11;14)(p13;q11) respectively in a causal factor in tumorigenesis. LMO1 has been found as a heterodimer with a 46 Kd protein in a T cell line derived from a childhood T-acute leukaemia. This 46 Kd protein is the LIM-binding protein LDB1/NLI. The latter is a phosphoprotein and binds to LMO1 in its phosphorylated state and essentially all the LMO1 and LDB1 protein in the T cell line is part of the complex. Therefore, the LMO1-LDB1 interaction is likely to be involved in tumorigenesis after LMO1 is ectopically expressed following chromosomal translocation in T cells prior to development of acute leukaemias.

Chromosomes, Human, Pair 11↗
PubMed1998

Identification of the LMO4 gene encoding an interaction partner of the LIM-binding protein LDB1/NLI1: a candidate for displacement by LMO proteins in T cell acute leukaemia.

The T cell oncogenes LMO1 and LMO2 are activated by distinct chromosomal translocations in childhood T cell acute leukaemias. Transgenic mouse models of this disease demonstrate that enforced expression of Lmo1 and Lmo2 cause T cell leukaemias with long latency and that Lmo2 expression leads to an inhibition of the T cell differentiation programme, prior to overt disease. These functions appear to be partly mediated by interaction of LMO1 or LMO2 with the LIM-binding protein LDB1/ NLI1. We have now identified a new member of the Lmo family, designated Lmo4, via its interaction with Ldb1. Lmo4 is widely expressed in mouse tissues, including adult thymus (mainly CD4, CD8-double positive T cells) and embryonic thymus (mainly CD4, CD8-double negative T cells). These characteristics imply that Ldb1-Lmo4 interaction may function in the T cell developmental programme and that enforced expression of LMO1 or LMO2 by chromosomal translocations or transgenesis may displace Lmo4 from this complex and thereby influence T cell differentiation prior to T cell tumour occurrence.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The oncogenic T cell LIM-protein Lmo2 forms part of a DNA-binding complex specifically in immature T cells.

The LIM-only protein LMO2 is expressed aberrantly in acute T-cell leukaemias as a result of the chromosomal translocations t(11;14) (p13;q11) or t(7;11) (q35;p13). In a transgenic model of tumorigenesis by Lmo2, T-cell acute leukaemias arise after an asymptomatic phase in which an accumulation of immature CD4(-) CD8(-) double negative thymocytes occurs. Possible molecular mechanisms underlying these effects have been investigated in T cells from Lmo2 transgenic mice. Isolation of DNA-binding sites by CASTing and band shift assays demonstrates the presence of an oligomeric complex involving Lmo2 which can bind to a bipartite DNA motif comprising two E-box sequences approximately 10 bp apart, which is distinct from that found in erythroid cells. This complex occurs in T-cell tumours and it is restricted to the immature CD4(- )CD8(-) thymocyte subset in asymptomatic transgenic mice. Thus, ectopic expression of Lmo2 by transgenesis, or by chromosomal translocations in humans, may result in the aberrant protein interactions causing abnormal regulation of gene expression, resulting in a blockage of T-cell differentiation and providing precursor cells for overt tumour formation.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis.

The LIM-finger protein Lmo2, which is activated in T cell leukemias by chromosomal translocations, is required for yolk sac erythropoiesis. Because Lmo2 null mutant mice die at embryonic day 9-10, it prevents an assessment of a role in other stages of hematopoiesis. We have now studied the hematopoietic contribution of homozygous mutant Lmo2 -/- mouse embryonic stem cells and found that Lmo2 -/- cells do not contribute to any hematopoietic lineage in adult chimeric mice, but reintroduction of an Lmo2-expression vector rescues the ability of Lmo2 null embryonic stem cells to contribute to all lineages tested. This disruption of hematopoiesis probably occurs because interaction of Lmo2 protein with factors such as Tal1/Scl is precluded. Thus, Lmo2 is necessary for early stages of hematopoiesis, and the Lmo2 master gene encodes a protein that has a central and crucial role in the hematopoietic development.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The T-cell oncogenic protein HOX11 activates Aldh1 expression in NIH 3T3 cells but represses its expression in mouse spleen development.

Hox11 is a homeobox gene essential for spleen formation in mice, since atrophy of the anlage of a developing spleen occurs in early embryonic development in Hox11 null mice. HOX11 is also expressed in a subset of T-cell acute leukemias after specific chromosomal translocations. Since the protein has a homeodomain and can activate transcription, it probably exerts at least some of its effects in vivo by regulation of target genes. Representational difference analysis has been used to isolate cDNA clones corresponding to mRNA species activated following stable expression of HOX11 in NIH 3T3 cells. The gene encoding the retinoic acid-synthesizing enzyme aldehyde dehydrogenase 1 (Aldh1), initially called Hdg-1, was found to be ectopically activated by HOX11 in this system. Study of Aldh1 gene expression during spleen development showed that the presence of Aldh1 mRNA inversely correlated with Hox11. Hox11 null mouse embryos have elevated Aldh1 mRNA in spleen primordia prior to atrophy, while Aldh1 seems to be repressed by Hox11 during organogenesis of the spleens of wild-type mice. This result suggests that expression of Aldh1 protein is negatively regulated by Hox11 and that abnormal expression of Aldh1 in Hox11 null mice may cause loss of splenic precursor cells by aberrant retinoic acid metabolism.

3T3 Cells↗
PubMed1998

Optimal activation of an endogenous gene by HOX11 requires the NH2-terminal 50 amino acids.

The HOX11 homeobox gene was first identified through studies of the t(7;10) and t(10;14) chromosomal translocations of acute T-cell leukemia. In addition, analysis of Hox11-/- mice has demonstrated a critical role for this gene in murine spleen development. A possible mode of in vivo function for the HOX11 protein in these two situations is regulation of target genes following DNA binding via the homeodomain, but little is known about how HOX11 regulates transcription in vivo. By performing transcriptional studies in yeast and mammalian one-hybrid systems, a modular transcriptional transactivation region at the NH2 terminus of HOX11 has been functionally dissected from other parts of the protein. This NH2-terminal region includes the previously identified short conserved Hep motif, which itself activates transcription in one-hybrid assays. The importance of the NH2-terminal region for the function of HOX11 in vivo was assayed by activating a HOX11-dependent gene in NIH 3T3 cells. Activation of this gene was found to be dependent upon an intact homeodomain in HOX11, but maximal activation was obtained only when the NH2-terminal 50 amino acids of HOX11 was present, showing that this region of HOX11 is important for in vivo transcriptional control of a chromosomal target gene.

3T3 Cells↗
PubMed1997

The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins.

The LIM-only protein Lmo2, activated by chromosomal translocations in T-cell leukaemias, is normally expressed in haematopoiesis. It interacts with TAL1 and GATA-1 proteins, but the function of the interaction is unexplained. We now show that in erythroid cells Lmo2 forms a novel DNA-binding complex, with GATA-1, TAL1 and E2A, and the recently identified LIM-binding protein Ldb1/NLI. This oligomeric complex binds to a unique, bipartite DNA motif comprising an E-box, CAGGTG, followed approximately 9 bp downstream by a GATA site. In vivo assembly of the DNA-binding complex requires interaction of all five proteins and establishes a transcriptional transactivating complex. These data demonstrate one function for the LIM-binding protein Ldb1 and establish a function for the LIM-only protein Lmo2 as an obligatory component of an oligomeric, DNA-binding complex which may play a role in haematopoiesis.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Chromosomal translocations and leukaemia: a role for LMO2 in T cell acute leukaemia, in transcription and in erythropoiesis.

The LMO2 gene associated with T cell acute leukaemia has been used as an example of a gene activated by association with the T cell receptor genes after chromosomal translocations. The gene is shown to encode a LIM protein which is involved in protein interactions and during normal haematopoiesis is necessary for erythroid development. LMO2 has been shown to cause tumours when aberrantly expressed and to be able to heterodimerise with TAL1 to facilitate tumour development.

Adaptor Proteins, Signal Transducing↗
PubMed1997

LIM-only protein Lmo2 forms a protein complex with erythroid transcription factor GATA-1.

The LIM-only protein Lmo2, originally identified as an oncogenic protein in human T cell leukemia, is essential for erythropoiesis. A possible role for Lmo2 in transcription during erythropoiesis has been investigated. Direct interaction of Lmo2 was observed in vitro and in vivo with the zinc finger transcription factor GATA-1, as well as with the basic helix-loop-helix (bHLH) transcription factor Tall. By using mammalian two-hybrid analysis, E47/Tall/Lmo2/GATA-1 protein complex could be demonstrated. Thus, a molecular link exists between three proteins crucial for erythropoiesis. This data suggest that variations in amounts of complexes involving Lmo2, Tall, and GATA-1 could be important for erythroid differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.

FUS (TLS) was first identified as the 5'-part of a fusion gene with CHOP (GADD153, DDIT3) in myxoid liposarcomas with t(12; 16)(q13; p11). Homologies were found with the EWS oncogene, which is rearranged in Ewing sarcomas and other neoplasias. The genomic structure of FUS shows extensive similarities with that of EWS, but the exon/intron structures differ in the 5' parts, and overall FUS is smaller than EWS. Exon 3 of FUS corresponds to exons 3 and 4 in EWS. FUS exons 4-6 correspond to EWS exons 5-8. Exons 7 to 15 of FUS are very similar to those in EWS, although the EWS exons are larger than the corresponding FUS exons. FUS and EWS were expressed in all tissues investigated. The transcripts were stable within the 160-min half-life experiments. No or little variation in FUS or EWS expression was seen when resting lymphocytes were activated. These observations indicate that FUS and EWS belong to the housekeeping type of genes. This view is supported by the presence of the housekeeping gene type of promoter region in both genes.

Amino Acid Sequence↗