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At least 19 recordsLinked to original sources
PubMed1993

The oncogenic potential of deregulated homeobox genes.

Homeobox genes encode DNA-binding proteins that regulate gene expression during embryonic development. Deregulation of homeobox gene expression has been invoked as the molecular basis of a number of leukemias. We now demonstrate, using in vitro and in vivo transformation assays, that the overexpression of homeobox genes is the basis for transformation and tumorigenesis. Thus, clustered homeobox genes related to Drosophila Hom genes (Hoxa-7, Hoxa-5, Hoxa-1, Hoxb-7, and Hoxc-8) as well as the homeobox genes Evx-1 and Cdx-1 constitute a new family of nuclear protooncogenes. This finding suggests that many homeobox genes regulating embryogenesis can--if deregulated--also contribute to tumorigenesis.

Animals↗
PubMed2004

Rapid evolution of mammalian X-linked testis-expressed homeobox genes.

Homeobox genes encode transcription factors that function in various developmental processes and are usually evolutionarily conserved in their sequences. However, two X-chromosome-linked testis-expressed homeobox genes, one from rodents and the other from fruit flies, are known to evolve rapidly under positive Darwinian selection. Here we report yet another case, from primates. TGIFLX is an X-linked homeobox gene that originated by retroposition of the autosomal gene TGIF2, most likely in a common ancestor of rodents and primates. While TGIF2 is ubiquitously expressed, TGIFLX is exclusively expressed in adult testis. A comparison of the TGIFLX sequences among 16 anthropoid primates revealed a significantly higher rate of nonsynonymous nucleotide substitution (d(N)) than synonymous substitution (d(S)), strongly suggesting the action of positive selection. Although the high d(N)/d(S) ratio is most evident outside the homeobox, the homeobox has a d(N)/d(S) of approximately 0.89 and includes two codons that are likely under selection. Furthermore, the rate of radical amino acid substitutions that alter amino acid charge is significantly greater than that of conservative substitutions, suggesting that the selection promotes diversity of the protein charge profile. More interestingly, an analysis of 64 orthologous homeobox genes from humans and mice shows substantially higher rates of amino acid substitution in X-linked testis-expressed genes than in other genes. These results suggest a general pattern of rapid evolution of mammalian X-linked testis-expressed homeobox genes. Although the physiological function of and the exact selective agent on TGIFLX and other rapidly evolving homeobox genes are unclear, the common expression pattern of these transcription factor genes led us to conjecture that the selection is related to one or more aspects of male reproduction and may contribute to speciation.

Amino Acid Sequence↗
PubMed1994

Pancreatic beta cells express a diverse set of homeobox genes.

Homeobox genes, which are found in all eukaryotic organisms, encode transcriptional regulators involved in cell-type differentiation and development. Several homeobox genes encoding homeodomain proteins that bind and activate the insulin gene promoter have been described. In an attempt to identify additional beta-cell homeodomain proteins, we designed primers based on the sequences of beta-cell homeobox genes cdx3 and lmx1 and the Drosophila homeodomain protein Antennapedia and used these primers to amplify inserts by PCR from an insulinoma cDNA library. The resulting amplification products include sequences encoding 10 distinct homeodomain proteins; 3 of these proteins have not been described previously. In addition, an insert was obtained encoding a splice variant of engrailed-2, a homeodomain protein previously identified in the central nervous system. Northern analysis revealed a distinct pattern of expression for each homeobox gene. Interestingly, the PCR-derived clones do not represent a complete sampling of the beta-cell library because no inserts encoding cdx3 or lmx1 protein were obtained. Beta cells probably express additional homeobox genes. The abundance and diversity of homeodomain proteins found in beta cells illustrate the remarkable complexity and redundancy of the machinery controlling beta-cell development and differentiation.

Amino Acid Sequence↗
PubMed1999

Distinct structural domains in the planarian brain defined by the expression of evolutionarily conserved homeobox genes.

Homeobox genes such as orthodenticle in Drosophila and its mouse homologues, Otx1 and Otx2, are known to be essential for rostral brain development. To investigate the molecular basis of brain evolution, we searched for otd/Otx-related homeobox genes in the planarian Dugesia japonica, and identified two genes, DjotxA and B, whose expression appears to be restricted to the cephalic ganglion (brain). DjotxA was expressed more medially, in the region containing the termini of the visual axons, and in the visual cells, suggesting involvement in establishment of the visual system. DjotxB was expressed in a discrete region just lateral to the DjotxA-positive domain, but not in the more lateral branch structures, which in turn are characterized by the expression of Djotp, a planarian homeobox gene related to mouse Orthopedia (Otp). In transverse sections of planarians, DjotxA and B expression were observed only at the anterior ends of the stumps, corresponding to the regional pattern of the regenerating brain. Our findings suggest that the planarian brain is composed of structurally distinct and functionally diverse domains which are defined by the discrete expression of the three evolutionarily conserved homeobox genes.

Amino Acid Sequence↗
PubMed1998

Patterning of the murine dentition by homeobox genes.

Homeobox genes have been shown to be important for the regulation of pattern formation of many systems during embryogenesis. Overlapping domains of Hox gene expression in the paraxial mesoderm have been suggested to create a combinatorial code of expression (Hox code) specifying the structures of individual segments such as the vertebrae. Hox genes are not expressed in the neural crest cells contributing to tooth formation, and so a Hox code can not be involved in patterning the dentition. It has previously been proposed that other, non-Hox homeobox genes may pattern the dentition. Expression data in this paper shows that there is a pattern of overlapping domains of homeobox gene expression in facial mesenchyme prior to the initiation of tooth development. We propose that expression of these genes constitutes an odontogenic homeobox code which patterns the dentition.

Animals↗
PubMed2000

Functions of LIM-homeobox genes.

Homeobox genes play fundamental roles in development. They can be subdivided into several subfamilies, one of which is the LIM-homeobox subfamily. The primary structure of LIM-homeobox genes has been remarkably conserved through evolution. Have their functions similarly been conserved? A host of new data has been derived from mutational analysis in diverse organisms, such as nematodes, flies and vertebrates. These studies have revealed a prominent involvement of LIM-homeodomain proteins in tissue patterning and differentiation, and their function in neural patterning is evident in all organisms studied to date. Here, we summarize the recent findings on LIM-homeobox gene function, compare the function of these genes from different organisms and describe specific co-factor requirements.

Animals↗
PubMed1991

Homeobox gene expression correlated with the bifurcation process of limb cartilage development.

The complex architecture of the limb cartilage pattern probably develops by the sequential segmentation and branching process of precartilaginous cell condensation under the control of positional signalling provided by the zone of polarizing activity (anteroposterior) and the apical ectodermal ridge (proximodistal). This signalling is monitored and interpreted in the mesenchymal cells and induces the position-specific response of subsets of genes. Homeobox genes may be responsible for the interpretation of signalling. A correlation between limb pattern and expression domains of the homeobox genes in the upstream region of Hox/Chox-4 has been proposed. We have analysed the spatial expression pattern of the Chox-1 genes during development of chick limb buds. In contrast to genes in Hox/Chox-4 expressed coordinately along the anteroposterior axis, homeobox genes in Chox-1 have unique and mutually exclusive expression domains along the proximodistal axis. We report here that the expression domains of the Chox-1 genes are closely related to the segmental structure of cartilage along the proximodistal axis, whereas the expression domains of the Chox-4 genes are related to the cartilage branching pattern.

Animals↗
PubMed1991

Cloning of a human homeobox gene that resembles a diverged Drosophila homeobox gene and is expressed in activated lymphocytes.

A new homeobox gene, HB24, has been isolated from a human B-lymphocyte cDNA library. Northern blot analysis of polyadenylated RNA purified from activated human B cells revealed a single mRNA transcript of approximately 2.3 kb. Two cDNA clones were sequenced and provided 2,250 nucleotides (nt) of DNA sequence information. There is a single methionine codon-initiated open reading frame of 1,458 nt in frame with a homeobox and a CAX repeat, and the open reading frame is predicted to encode a protein of 51,659 daltons. When the homeodomain from HB24 was compared to known mammalian and Drosophila homeodomains it was found to be only moderately conserved, but when it was compared to a highly diverged Drosophila homeodomain, H2.0, it was found to be 80% identical. The HB24 mRNA was absent or present at low levels in normal B and T lymphocytes; however, with the appropriate activation signal HB24 mRNA was induced within several hours even in the presence of cycloheximide. Characterization of HB24 expression in lymphoid and select developing tissues was performed by in situ hybridization. Positive hybridization was found in thymus, tonsil, bone marrow, developing vessels, and in fetal brain. HB24 is likely to have an important role in lymphocytes as well as in certain developing tissues.

Amino Acid Sequence↗
PubMed2005

A concerted action of a paired-type homeobox gene, aristaless, and a homolog of Hox11/tlx homeobox gene, clawless, is essential for the distal tip development of the Drosophila leg.

The subdivision of the developing field by region-specific expression of genes encoding transcription factors is an essential step during appendage development in arthropod and vertebrates. In Drosophila leg development, the distal-most region (pretarsus) is specified by the expression of homeobox genes, aristaless and Lim1, and its immediate neighbor (distal tarsus) is specified by the expression of a pair of Bar homeobox genes. Here, we show that one additional gene, clawless, which is a homolog of vertebrate Hox11/tlx homeobox gene family and formerly known as C15, is specifically expressed in the pretarsus and cooperatively acts with aristaless to repress Bar and possibly to activate Lim1. Similar to aristaless, the maximal expression of clawless requires Lim1 and its co-factor, Chip. Bar attenuates aristaless and clawless expression through Lim1 repression. Aristaless and Clawless proteins form a complex capable of binding to specific DNA targets, which cannot be well recognized solely by Aristaless or Clawless.

Animals↗
PubMed1995

Structure and function of the HOX A1 human homeobox gene cDNA.

Homeobox genes code for transcription factors and are arranged in clusters, named A, B, C and D, found on four separate chromosomes in vertebrates. They contain a homeobox DNA sequence which codes for the homeodomain, a region of amino acids responsible for the DNA binding exhibited by these proteins. During embryonic development, the homeobox genes are both spatially and temporally regulated. In teratocarcinoma cell cultures, homeobox genes are regulated by retinoic acid (RA). The cDNAs from the first gene in the human HOX A cluster, HOX A1 (1.6), were cloned and the nucleotide sequence of a full-length cDNA was determined. It is highly homologous to its murine counterpart. Another HOX A1 cDNA was cloned, corresponding to an alternatively spliced form. In vitro translation of the full-length cDNA clone gave rise to a protein of 36 kDa. In PA-1 human teratocarcinoma cells HOX A1 is the earliest HOX A gene to be expressed after treatment with RA. To test whether HOX A1 could function as a early regulator of other HOX A cluster genes, we cotransfected into PA-1 human teratocarcinoma cells sense and antisense HOX A1 cDNAs expressed from an SV40 promoter with a 5.4-kb RA-sensitive HOX A4 (1.4) promoter-cat reporter. We found no effect of HOX A1 on the HOX A4 promoter. However, cotransfection of HOX A5 (1.3) was able to inhibit the HOX A4 promoter activity.

Alternative Splicing↗
PubMed1988

A novel, tissue-specific, Drosophila homeobox gene.

The homeobox gene family of Drosophila appears to control a variety of position-specific patterning decisions during embryonic and imaginal development. Most of these patterning decisions determine groups of cells on the anterior-posterior axis of the Drosophila germ band. We have isolated a novel homeobox gene from Drosophila, designated H2.0. H2.0 has the most diverged homeobox so far characterized in metazoa, and, in contrast to all previously isolated homeobox genes, H2.0 exhibits a tissue-specific pattern of expression. The cells that accumulate transcripts for this novel gene correspond to the visceral musculature and its anlagen.

Amino Acid Sequence↗
PubMed1994

Genomic organization and chromosome localization of the murine homeobox gene Pmx.

Homeobox genes are expressed in very specific temporal and spatial patterns and function as transcriptional regulators of developmental processes. The murine homeobox gene, Pmx (paired mesoderm homeobox), is expressed in a mesodermally restricted pattern in embryos and most abundantly in cardiac, skeletal, and smooth muscle tissues in adults. Previously, this murine gene was named K-2 and mHox, while the human homolog was named Phox1. In this report, the localization of Pmx has been determined by interspecific backcross analysis. The Pmx gene is located on Chromosome 1, approximately 3.3 cM distal to the Gsh-4 homeobox locus. The sequence of the Pmx transcript has been extended toward the 5' end and corresponds in size to one of the transcripts previously detected by Northern blot analysis. Sequence analysis indicates that Pmx is the first characterized mammalian gene to encode a paired type homeodomain, but not a paired domain. The Pmx gene includes at least five exons spanning a minimum of 60 kb of genomic DNA, making this the largest known murine homeobox gene.

Animals↗
PubMed2005

Rhox: a new homeobox gene cluster.

Homeobox genes encode transcription factors notable for their ability to regulate embryogenesis. Here, we report the discovery of a cluster of 12 related homeobox genes on the X chromosome expressed in male and female reproductive tissues in adult mice. These reproductive homeobox on the X chromosome (Rhox) genes are expressed in a cell type-specific manner; several are hormonally regulated, and their expression pattern during postnatal testis development corresponds to their chromosomal position. Most of the Rhox genes are expressed in Sertoli cells, the nurse cells in direct contact with developing male germ cells, suggesting that they regulate the expression of somatic-cell gene products critical for germ cell development. In support of this, targeted disruption of Rhox5 increased male germ cell apoptosis and reduced sperm production, sperm motility, and fertility. Identification of this family of homeobox genes provides an opportunity to study colinear gene regulation and the transcriptional control of reproduction.

Animals↗
PubMed1995

Sequence and evolutionary conservation of the murine Gbx-2 homeobox gene.

The homeobox gene family is divided into classes based on similarity of sequence across the homeodomain. Representative members of discrete classes are often conserved widely throughout evolution and this can extend to their genomic organisation and biological function. In this paper we report the first complete cDNA sequence of a member of the GBX class of homeobox genes, the murine gene Gbx-2. Sequence comparisons indicate that this homeodomain class is highly conserved within vertebrates. The homeodomain differs at only three positions out of 60 and these can be used to subdivide the GBX class homeodomains into 2 sub-classes.

Amino Acid Sequence↗
PubMed2003

Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13).

The NUP98 gene at 11p15 is known to be fused to DDX10, HOXA9, HOXA11, HOXA13, HOXD11, HOXD13, LEDGF, NSD1, NSD3, PMX1, RAP1GDS1, and TOP1 in various hematologic malignancies. The common theme in all NUP98 chimeras is a transcript consisting of the 5' part of NUP98 and the 3' portion of the partner gene; however, apart from the frequent fusion to different homeobox genes, there is no apparent similarity among the other partners. We here report a de novo acute myeloid leukemia with a t(11;12)(p15;q13), resulting in a novel NUP98/HOXC13 fusion. Fluorescence in situ hybridization analyses, by the use of probes covering NUP98 and the HOXC gene cluster at 12q13, revealed a fusion signal at the der(11)t(11;12), indicating a NUP98/HOXC chimera, whereas no fusion was found on the der(12)t(11;12), suggesting that the translocation was accompanied by a deletion of the reciprocal fusion gene. Reverse transcription-PCR and sequence analyses showed that exon 16 (nucleotide 2290) of NUP98 was fused in-frame with exon 2 (nucleotide 852) of HOXC13. Neither the HOXC13/NUP98 transcript nor the normal HOXC13 was expressed. The present results, together with previous studies of NUP98/homeobox gene fusions, strongly indicate that NUP98/HOXC13 is of pathogenetic importance in t(11;12)-positive acute myeloid leukemia.

Acute Disease↗
PubMed1997

Lhx4, a LIM homeobox gene.

LIM homeobox genes are well conserved in evolution and play important roles as transcriptional regulators of embryonic development. Here we report on the structure of LIM domains of the mouse Lhx4 (Gsh4) gene. The cDNA was generated by modified reverse transcription-PCR from midgestation embryo templates, using a degenerate consensus primer. The deduced amino acid sequence of the first LIM domain reveals 77% identity and that of the second domain reveals 86% identity with the corresponding sequences of the closely related Lhx3 gene. In addition, there is 38-56% similarity to other members of the Lhx gene family. The LIM consensus sequence is well conserved in Lhx4.

Amino Acid Sequence↗
PubMed2002

Mbx, a novel mouse homeobox gene.

The homeobox gene Mbxis thought to play important roles in the development of eyes and tectum in zebrafish. We isolated mouse Mbx cDNA and analyzed its expression pattern during early mouse embryogenesis. Expression is predominantly restricted to the midbrain region at E9.5. At subsequent stages of development, Mbx transcripts were also found in the forebrain in addition to midbrain. Thus, the Mbx gene provides a useful molecular marker for early mouse midbrain development and may play a critical role in brain development.

Amino Acid Sequence↗
PubMed1998

The rough sheath2 gene negatively regulates homeobox gene expression during maize leaf development.

Leaves of higher plants are produced in a sequential manner through the differentiation of cells that are derived from the shoot apical meristem. Current evidence suggests that this transition from meristematic to leaf cell fate requires the down-regulation of knotted1-like homeobox (knox) gene expression. If knox gene expression is not repressed, overall leaf shape and cellular differentiation within the leaf are perturbed. In order to identify genes that are required for the aquisition of leaf cell fates, we have genetically screened for recessive mutations that confer phenotypes similar to dominant mutations (e.g. Knotted1 and Rough sheath1) that result in the ectopic expression of class I knox genes. Independently derived mutations at the rough sheath2 (rs2) locus condition a range of pleiotropic leaf, node and internode phenotypes that are sensitive to genetic background and environment. Phenotypes include dwarfism, leaf twisting, disorganized differentiation of the blade-sheath boundary, aberrant vascular patterning and the generation of semi-bladeless leaves. knox genes are initially repressed in rs2 mutants as leaf founder cells are recruited in the meristem. However, this repression is often incomplete and is not maintained as the leaf progresses through developement. Expression studies indicate that three knox genes are ectopically or over-expressed in developing primordia and in mature leaves. We therefore propose that the rs2 gene product acts to repress knox gene expression (either directly or indirectly) and that rs2 gene action is essential for the elaboration of normal leaf morphology.

Cell Differentiation↗