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T H Rabbitts

Publications and source records attributed to T H Rabbitts.

At least 19 recordsLinked to original sources
PubMed1992

The rhombotin gene family encode related LIM-domain proteins whose differing expression suggests multiple roles in mouse development.

The rhombotin (RBTN1 or Ttg-1) gene was first identified at a chromosome translocation in a T-cell acute leukaemia and later used to isolate two related genes (RBTN2 or Ttg-2 and RBTN3). Complete characterization of these genes in man and mouse shows that all three encode cysteine-rich proteins with typical LIM domains. RBTN1 and RBTN3-derived proteins have 98% identity in the LIM domains but are located on separate chromosomes in man and in mouse while RBTN1 and RBTN2, both located on human chromosome 11p but are on separate chromosomes in mouse, are only 48% identical in this part of the protein. The exon organization of RBTN1 and RBTN3 genes are similar, both having an intron, absent from the RBTN2 gene, in the LIM2-encoding region. The remarkable similarity between rbtn-1 and rbtn-3 proteins is parallelled in their expression patterns in mouse development, since both genes show high expression in restricted areas of the brain, but little lymphoid expression. rbtn-2 expression, however, is more ubiquitous. This gene shows a low level of thymus expression but high expression in fetal liver, adult spleen and B-cell lines, consistent with a role in B-cell development. These results suggest multiple cellular targets for the action of these proteins during development.

Adult↗
PubMed1992

Immunoglobulin VH-T cell receptor C alpha fusion mRNA resulting from chromosome inversion include the T cell-associated 5' exon ET.

A human T cell lymphoma has been described in which an inversion of chromosome 14 results in fusion of an immunoglobulin heavy chain VH with a T cell receptor J alpha segment, potentially resulting in a chimeric protein with immunoglobulin VH region recognition plus T cell receptor effector functions. Examination of the mRNA species expressed from the IgT gene in this lymphoma shows a variety of forms but all IgT mRNA include the T cell-specific exon, ET, previously located in the distal part of the VH locus. In such mRNA species, the normal leader exon of the Ig VH segment, which encodes most of the hydrophobic signal peptide, is replaced by the short ET exon encoding mainly non-hydrophobic residues. Two forms of this mRNA exist which lack the Ig VH leader sequence and thus potentially yield non-membrane proteins in the T cell lymphoma.

Alternative Splicing↗
PubMed1992

Molecular analysis of a new translocation, t(X;14)(q28;q11), in premalignancy and in leukaemia associated with ataxia telangiectasia.

The disease ataxia telangiectasia (A-T) is a multifaceted disorder in which patients have an increased chance of developing a T-cell leukaemia, often with abnormalities of chromosome 14, but sometimes with rare translocations, like t(X;14)(q28;q11). We describe the cloning of the breakpoint of one such novel t(X;14) from an A-T patient. The translocation breaks within the T cell receptor alpha chain gene on chromosome 14 at band q11 and in a region of the X chromosome, within about 1 Mb of the telomere of the long arm. The patient subsequently developed T-cell prolymphocytic leukaemia (T-PLL), and molecular examination showed that the tumour cells carried the same t(X;14) breakpoint as that cloned from the premalignant cells. The same breakpoint could be detected in blood samples taken as much as 5 years prior to diagnosis of T-PLL. This suggests a role for the abnormality in the tumour development in this patient but implies that other mutational events were necessary for overt disease to become manifest.

Adult↗
PubMed1992

Human RAG2, like RAG1, is on chromosome 11 band p13 and therefore not linked to ataxia telangiectasia complementation groups.

Ataxia telangiectasia (A-T) is an inherited, recessive, cancer-prone disease with associated immunodeficiency and chromosome abnormalities involving TCR loci. The latter phenomena implicate errors of the enzyme(s) responsible for assembly of antigen receptor genes (recombinase) in disease pathogenesis. Here we report the location of a human recombination activating gene (RAG2), in addition to RAG1, on chromosome 11, band p13, thereby formally demonstrating linkage of these genes in humans and showing that they are not linked to the known locus responsible for the A-T syndrome.

Ataxia Telangiectasia↗
PubMed1992

T-cell acute lymphoblastic lymphoma induced in transgenic mice by the RBTN1 and RBTN2 LIM-domain genes.

Two members of the RBTN gene family, RBTN1/Ttg-1 and RBTN2/Ttg-2, were found by their association with T-cell tumour-specific chromosomal translocations and are thought to be involved in the aetiology of such T-cell tumours. Here a transgenic mouse model is described in which T-cell tumours are induced by the presence of RBTN1 and RBTN2 transgenes that direct expression in thymus-derived cells. The latency period for lymphoid tumour appearance is variable, and tumours occur in a small proportion of transgenic animals that develop T-cell acute lymphoblastic malignancies. No significant increase in the rate of tumour development was observed in RBTN1 transgenic mice infected with Moloney murine leukaemia virus, nor did tumours arise in mice bearing a construct in which RBTN1 was expressed from the insulin transcriptional promoter. These data, which provide formal proof of the oncogenic activity of these genes, suggest that aberrant expression of transcription factor genes, such as RBTN1 and RBTN2, functions in tumour aetiology by disturbing some aspect of T-cell differentiation.

Animals↗
PubMed1991

Molecular cloning of putative odorant-binding and odorant-metabolizing proteins.

Olfactory reception occurs via the interaction of odorants with the chemosensory cilia of the olfactory receptor cells located in the nasal epithelium. The cDNA clones from mRNA specific to olfactory mucosa were studied. One of these clones, OBPII, encodes a secretory protein with significant homology to odorant-binding protein (OBP), a protein with broad odorant-binding ability, and is expressed in the lateral nasal gland, which is the site of expression of OBP. The OBPII sequence also shows significant homology to the VEG protein, which is thought to be involved in taste transduction. OBPII is a new member of the lipophilic molecule carrier protein family. The second cDNA clone encodes a novel homologue of glutathione peroxidase, an enzyme involved in cellular biotransformation pathways. Its expression appears to be localized to the Bowman's glands, the site of several previously identified olfactory-specific biotransformation enzymes.

Amino Acid Sequence↗
PubMed1991

HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24.

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.

Amino Acid Sequence↗
PubMed1991

The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13.

A chromosomal translocation in a T-cell leukemia involving the short arm of human chromosome 11 at band 11p15 disrupts the rhombotin gene. This gene encodes a protein with duplicated cysteine-rich regions called LIM domains, which show homology to zinc-binding proteins and to iron-sulfur centers of ferredoxins. Two homologues of the rhombotin gene have now been isolated. One of these, designated Rhom-2, is located on human chromosome 11 at band 11p13, where a cluster of T-cell leukemia-specific translocations occur; all translocation breakpoints at 11p13 are upstream of the Rhom-2 gene. Human and mouse Rhom-2 are highly conserved and, like rhombotin, encode two tandem cysteine-rich LIM domains. Rhom-2 mRNA is expressed in early mouse development in central nervous system, lung, kidney, liver, and spleen but only very low levels occur in thymus. The other gene, designated Rhom-3, is not on chromosome 11 but also retains homology to the LIM domain of rhombotin. Since the Rhom-2 gene is such a common site of chromosomal damage in T-cell tumors, the consistency of translocations near the rhombotin gene was further examined. A second translocation adjacent to rhombotin was found and at the same position as in the previous example. Therefore, chromosome bands 11p15 (rhombotin) and 11p13 (Rhom-2) are consistent sites of chromosome translocation in T-cell leukemia, with the 11p15 target more rarely involved. The results define the rhombotin gene family as a class of T-cell oncogenes with duplicated cysteine-rich LIM domains.

Amino Acid Sequence↗
PubMed1991

A simple technique for generating probes for RNA in situ hybridization: an adjunct to genome mapping exemplified by the RAG-1/RAG-2 gene cluster.

Two major problems have to be solved in studies of genes near breakpoints of chromosome abnormalities and in large-scale genomic mapping projects: (i) the identification of genes within the large amount on nontranscribed DNA and (ii) the determination of the tissues in which the identified genes are transcribed. In situ hybridization to mRNA is ideally suited to assess gene expression in all tissues but probe preparation presents major difficulties for adapting the technique for rapid screening. Here, we present a procedure to easily generate strand-specific DNA probes for in situ hybridization. In this method, a DNA fragment to be tested in uniformly labeled, denatured, and prehybridized to an excess of competitor single-stranded DNA corresponding to either positive or negative strands of the test fragment. No sequence information is needed. The prehybridized mixture is used directly for hybridization to whole embryo or tissue sections. We demonstrate the utility of this approach for any nonrepetitive fragment by using cDNA probes, intronless genomic probes, or genomic probes comprising transcribed and nontranscribed DNA. As an example, we show that mRNA for the recombination-activating genes (RAG) RAG-1 and RAG-2 is found in thymus of dE16 mouse embryos. Within the thymus, high levels of expression of RAG-1 and RAG-2 are detectable in the cortex but not in the medullary region. This supports the view that RAG-1 and RAG-2 expression is associated with cells known to actively rearrange antigen receptor loci.

Animals↗
PubMed1991

Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus.

In order to study the requirements for a human antibody repertoire to be engineered in transgenic animals, we have created mouse strains that express human immunoglobulin genes from 100 kb of cosmid DNA. Undisrupted integration of the human DNA in the mouse germ line, encoding germ-line V,D,J and the Cmu constant region, was achieved, and proved sufficient for the production of human IgM in the mouse serum. Co-integration of one cosmid (containing the VH6 gene and a 36-kb region of the J-proximal D cluster) with a second cosmid (containing VH26, a further 38-kb of the D cluster, JH and Cmu) results in V-D-J rearrangements in the transgenic mice, similar to those seen in human DNA, were found only in spleen but not in thymus. Random hybridomas made from these transgenic mice show heterogeneous rearrangements of the human transgenes. Sequences of V-D-J units derived from transgene rearrangements reveal extensive N-region and apparent D segment diversity. These results show that utilisation of human Ig genomic segments does occur in transgenic mice, paving the way for the derivation of a mouse strain that makes authentic human antibodies from inserted heavy and light chain gene loci.

Animals↗
PubMed1991

Novel genes for potential ligand-binding proteins in subregions of the olfactory mucosa.

Odorant detection is specifically mediated via receptor neurons in the olfactory mucosa but is a complex process involving a number of different cell types producing proteins of differing function. We have used the technique of subtractive hybridization cDNA cloning to identify novel genes expressed exclusively in the olfactory mucosa which may play a role in olfaction. Ten distinct groups of cDNA clones were identified which corresponded to mRNA transcripts highly expressed in rat olfactory mucosa but undetectable in thymus, kidney, lung, brain, spleen and liver. Some of these clones identify substructures in the mucosal tissue for which no other probes are currently available. Others identify novel mRNA species in the Bowman's glands. The predicted proteins for three of these clones are homologous to proteins which bind to either lipopolysaccharides (RYA3 and RY2G5) or to polychlorinated biphenyls (RYD5). In addition, while RYA3 and RY2G5 are highly homologous, they appear to be expressed in different parts of the mucosal tissue. The sequence homologies and subanatomical location of expression suggest that these proteins might interact with odorants before or after specific recognition by odorant receptors. Therefore, the olfactory mucosa may possess diverse, functionally-distinct odorant-binding proteins which recognize and bind separate classes of odorants.

Amino Acid Sequence↗
PubMed1991

A study of chromosome 11p13 translocations involving TCR beta and TCR delta in human T cell leukaemia.

A frequent site of translocation damage in human T-ALL has been localized to a specific region of chromosome band 11p13. Five new T-ALL cases are described which break in the major T-ALLbcr region of 11p13, two involving a novel translocation t(7;11)(q35;p13), with breakage at the T cell receptor (TCR) beta gene from 7q35, and three involving TCR delta from 14q11 in the more common t(11;14)(p13;q11). Analysis of the mechanism of one T-ALLbcr/TCR beta translocation and a previously described t(11;14)(p13;q11) was conducted by genomic cloning of translocation breakpoints, using the polymerase chain reaction (PCR). Both seem to have occurred by recombinase error, but only the t(7;11) showed sequence-specific joining. Nonetheless recombinase mediation of the t(11;14) is implied by the presence of N-region addition (a hallmark of recombinase joins) on both derivative chromosomes. These observations reinforce the view that translocations in the T-ALLbcr region of chromosome 11p13 are a major lesion in human T-ALL. In addition, these can occur by mimicry of VDJ joining, but sequence specificity is not obligatory.

Base Sequence↗
PubMed1991

Developmentally regulated and tissue specific expression of mRNAs encoding the two alternative forms of the LIM domain oncogene rhombotin: evidence for thymus expression.

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.

Animals↗
PubMed1990

LIM domains.

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Animals↗