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F Meijlink

Publications and source records attributed to F Meijlink.

32 records · Page 2Linked to original sources
PubMed1992

Mammalian homeobox genes in normal development and neoplasia.

This review aims at providing an evaluation of the currently available data concerning the role of homeobox genes in mammalian embryonic pattern formation, and their involvement in oncogenic processes. The literature dealing with mouse and human homeobox genes is covered, with some excursions into Xenopus and chicken work because studies regarding particular aspects of development in the latter systems often complement those in mammals. Other studies in amphibians, chicken, and fish are omitted as they fall outside the scope of this survey devoted to mammalian genes. Emphasis is placed on expression and regulation during normal embryogenesis, on present hypotheses regarding gene function, on effects on development of modifying the expression patterns, and on observed aberrations in structure or expression associated with and possibly causally linked to neoplasia. The studies specifically dealing with the structure of the homeodomain and the mechanism of its interactions with DNA, which have been recently reviewed, are not considered here. The most thoroughly studied mammalian homeobox genes bear sequence homology to the Drosophila Antennapedia (Antp) homeotic gene and are thought to be involved in determination of regional identity along the anteroposterior (A-P) axis. Studies on these genes, the HOX genes, are oftem compared with related investigations in flies. In addition to the HOX genes, a number of genes containing a homeobox related to that in other Drosophila developmental control genes have been isolated from the mammalian genome and are being intensively studied. Homeodomains divergent from the Antp prototype have been discovered in an increasing number of transcription factors. Some of these may play a crucial role in local pattern formation, while others are tissue-specific or ubiquitous transcription regulators. As is unsurprising of genes, whose products regulate transcription, some of the homeobox-containing genes have been associated with malignancy, usually on the basis of abnormal structure, or deletions found to occur in tumor cells. The degree of probability that these mutated forms were causative in the generation of the tumors in which they were found is discussed.

Amino Acid Sequence↗
PubMed1991

Cloning of murine TCF-1, a T cell-specific transcription factor interacting with functional motifs in the CD3-epsilon and T cell receptor alpha enhancers.

CD3-epsilon gene expression is confined to the T cell lineage. We have recently identified and cloned a human transcription factor, TCF-1, that binds to a functional element in the T lymphocyte-specific enhancer of CD3-epsilon. In a panel of human cell lines, TCF-1 expression was restricted to T lineage cells. TCF-1 belonged to a novel family of genes that contain the so-called high mobility group 1 (HMG) box. Here we report the cloning of murine TCF-1. Two splice alternatives were identified that were not previously observed in human TCF-1. Murine and human TCF-1 displayed a 95.5% overall amino acid homology. Recombinant murine and human TCF-1 recognized the same sequence motif in the CD3-epsilon enhancer as judged by gel retardation and methylation interference assays. With the murine cDNA clones several aspects of TCF-1 were analyzed. First, deletion analysis revealed that a region of TCF-1 containing the HMG box was sufficient for sequence-specific binding. Second, by high stringency Northern blotting and in situ hybridization, TCF-1 expression was shown to be confined to the thymus and to the T cell areas of the spleen. Third, TCF-1 bound specifically to a functional T cell-specific element in the T cell receptor alpha (TCR-alpha) enhancer. The T lineage-specific expression and the affinity for functional motifs in the TCR-alpha and CD3-epsilon enhancers imply an important role for TCF-1 in the establishment of the mature T cell phenotype.

Amino Acid Sequence↗
PubMed1991

Characterization of the murine Hox-2.3 promoter: involvement of the transcription factor USF (MLTF).

The murine homeobox-containing gene Hox-2.3 contains a basal promoter in a 210-bp region upstream of the transcription start site. In vitro studies of DNA-protein interactions in this region, and in a 1.3-kb upstream region which is known to play a role in tissue specific expression in vivo, led to the identification of DNA elements interacting with nuclear proteins from embryocarcinoma cells. Among the factors binding to the basal promoter is the upstream stimulating factor (USF), also known as major late transcription factor (MLTF). A single point mutation in its binding site abolishes binding in vitro and leads to 50% reduction of the transcriptional activity as measured in receptor gene experiments, showing that it is an activator of Hox-2.3 expression.

Animals↗
PubMed1991

The mouse homeobox gene, S8, is expressed during embryogenesis predominantly in mesenchyme.

The murine S8 gene, originally identified by Kongsuwan et al. [EMBO J. 7(1988)2131-2138] encodes a homeodomain which resembles those of the paired family. We studied the expression pattern during mid-gestation embryogenesis of S8 by in situ hybridization. Expression was detected locally in craniofacial mesenchyme, in the limb, the heart and the somites and sclerotomes all along the axis, and was absent from the central and peripheral nervous system, splanchnopleure, and endodermal derivatives. This pattern differs considerably from that of most previously described homeobox containing genes. By genetic analysis, the gene was located on chromosome 2, about 20 cM from the HOX-4 cluster.

Amino Acid Sequence↗
PubMed1990

Hox-2.3 upstream sequences mediate lacZ expression in intermediate mesoderm derivatives of transgenic mice.

The mouse Hox-2.3 gene contains an Antp-like homeobox sequence and is expressed in a spatially restricted anteroposterior domain during development. To study the molecular basis of this differential gene regulation, we set out to characterize the cis-regulatory elements mediating Hox-2.3 expression during embryogenesis. We show that a fragment extending 1316 base pairs (bp) upstream of the transcription start site, thus corresponding to the Hox-2.4/Hox-2.3 intergenic sequences is capable of mediating luciferase gene transcription in transfected cells in vitro and lacZ expression in transgenic mice. The beta-galactosidase-staining pattern in embryos was found to be strikingly similar to the Hox-2.3 in situ hybridization pattern in intermediate mesoderm derivatives: high levels of both Hox-2.3 transcripts and beta-galactosidase activity were found in the mesonephric duct-derived epithelium of the meso- and metanephric kidney and associated ducts, from the time these structures first appeared on throughout development. The transgene apparently lacks sequences needed for correct Hox-2.3 expression in somitic and lateral plate mesoderm and in neurectoderm. These results document the involvement of distinct regulatory elements in Hox gene expression in subsets of cells with distinct developmental fate, situated at similar positions along the anteroposterior axis of the embryo.

Animals↗
PubMed1989

Isolation of the Xenopus homolog of int-1/wingless and expression during neurula stages of early development.

We have isolated the Xenopus homolog (Xint-1) of the mouse protooncogene int-1 from a neurula stage 17 cDNA library. The deduced protein sequence of Xint-1 includes 371 amino acids. The Xint-1 protein is more similar to the mammalian int-1 product (69%), than to the Drosophila counterpart of int-1, wingless (50%). Xint-1 shares several characteristics of secreted proteins with the other int-1 homologs: it has a hydrophobic leader, multiple conserved potential N-linked glycosylation sites and is rich in cysteine residues. All 23 cysteines are conserved in the three proteins. Xint-1 is transiently expressed during the neurula stages of early Xenopus development.

Amino Acid Sequence↗
PubMed1987

A mouse homeobox containing gene on chromosome 11: sequence and tissue-specific expression.

We have molecularly cloned a mouse homeobox containing gene by isolating cDNA and genomic clones. The gene is located in a previously described cluster on chromosome 11 (Hart et al. (1985) Cell 43, 9-18) and was identified as the Hox2.3 gene. We present the complete mRNA sequence of this gene and describe similarities to other homeobox containing genes, among which its human homologue, the cl gene. High expression of the Hox2.3 gene was found in kidney, testis, and spinal cord of adult mice, in the spinal cord of 12.5-17.5 day embryos and in differentiating EC cells depending on their treatment. Three different treatments of the pluripotent EC cell line P19, each leading to the induction of a specific differentiation pathway, resulted in all cases in induction of Hox2.3; however, major quantitative differences in this response were observed.

Amino Acid Sequence↗
PubMed1987

A new repetitive element of the CR1 family downstream of the chicken vitellogenin gene.

We have analyzed a repetitive DNA sequence found in the 3'-flanking region of the chicken vitellogenin gene. By its sequence, the repetitive DNA has been identified as a hitherto unreported member of the chicken CR1 family of repetitive elements. The CR1 sequence displays the structural characteristics of a long terminal repeat located at the 3' end of an avian retrovirus. The CR1 element lies 2.2 kb downstream of the vitellogenin gene and 'points' away from the gene rather than toward it. In this respect, this element differs from other CR1 repeats. The CR1 element is embedded in a region showing changes in chromatin structure implying a potential role for this sequence in determining the structural state of the local chromatin.

Alpharetrovirus↗
PubMed1987

Abundant expression of homeobox genes in mouse embryonal carcinoma cells correlates with chemically induced differentiation.

Mammalian homeobox-containing genes might play a role in embryonal pattern formation. In favor of this view is the recently reported expression of such genes during mouse embryogenesis [Manley, J. L. & Levine, M. S. (1985) Cell 43, 1-2]. The embryo-derived stem cells and in particular the pluripotent embryonal carcinoma (EC) cell lines are generally considered as a valid model of early mouse development. Homeobox-containing genes were shown to be expressed in differentiating EC cells. We have analyzed the expression of several of these genes in three EC cell lines triggered to differentiate by alternative treatments in the presence or in the absence of retinoic acid. In both types of conditions, C17S1 (clone 1003) and PCC7.S Aza R1 EC cells were induced to differentiate into mainly neurones, and PSA-1 EC cells were induced to differentiate into a large spectrum of tissue derivatives. Induction to high levels of expression of several homeobox-containing genes during differentiation occurs only in the presence of retinoic acid. Nonchemical treatment triggering differentiation does not lead to detectable expression of these genes. Accumulation to high amounts of homeobox-containing gene transcripts in these experiments seems to correlate with retinoic acid-induced EC cell differentiation rather than with EC cell differentiation as such.

Animals↗
PubMed1987

The mouse Hox2.3 homeobox-containing gene: regulation in differentiating pluripotent stem cells and expression pattern in embryos.

Genomic and cDNA clones of the mouse Hox2.3 gene have been isolated. Expression of this gene was characterized in differentiating embryonal carcinoma (EC) and embryonic stem (ES) cells, and in the 13.5-day embryo. Hox2.3 is expressed at a very low level, if at all, in undifferentiated ES and EC cells. As previously reported for the Hox1.1 and Hox2.1 genes, differentiation of pluripotent stem cells induced by a nonchemical method is not accompanied by strong accumulation of Hox2.3 transcripts. Treatment of the stem cells with a chemical inducer like retinoic acid (RA), and also hexamethylenebisacetamide (HMBA), or 5-bromo-2'-deoxyuridine (BUdR), simultaneously accelerates differentiation and stimulates accumulation of Hox2.3 mRNA to high levels. Addition of RA several days after the cells have been induced to differentiate by a nonchemical method induces Hox2.3-transcript accumulation as well. For comparison, expression of the En-1 gene, which contains a homeobox belonging to a different class from that of the Antennapedia-related Hox1.1, Hox2.1, and Hox2.3 genes, was analyzed. The En-1 gene was found also to be sensitive to this regulation by chemical inducers of differentiation. It was observed that treatment of undifferentiated EC cells with the inhibitor of protein synthesis cycloheximide resulted in slight accumulation of Hox2.3 mRNA, suggesting the involvement of a short-lived protein in keeping the level of homeobox-gene transcription low in EC cells. The highest level of Hox2.3 transcripts in 13.5-day embryos in vivo was observed in the spinal cord. Comparison with the expression pattern of three other homeobox genes revealed overlapping gradients of mRNA along the longitudinal brain-spinal-cord axis. An important question is that of the molecular basis for such a spatially restricted accumulation of homeobox transcripts. Hox2.3 is expressed at a much lower level in rat and mouse embryonic midbrain than in spinal cord in vivo. We have shown that addition of RA to primary cultures of cells from rat embryo mesencephalon leads to strong accumulation of Hox2.3 mRNA. A possible interpretation is that RA mimics one or more spatially restricted effectors, accounting for the local accumulation of Hox2.3 transcripts in the embryonic central nervous system. Control of Hox2.3 gene expression in vivo may obey some similar mechanisms as in chemically stimulated EC and ES cells in vitro.

Acetamides↗
PubMed1985

Identification of a transcriptional enhancer element upstream from the proto-oncogene fos.

Sequences upstream from the proto-oncogene fos were shown to be essential for its transcription. Transient expression of the chloramphenicol acetyl-transferase (CAT) gene linked to upstream sequences of the fos gene including its promoter reveals that sequences located 64 to 404 base pairs 5' to the fos cap site contain a typical transcriptional enhancer. Moreover, these enhancer sequences, which are strikingly conserved between mouse and human fos genes, coincide with a deoxyribonuclease I-hypersensitive site in the chromatin. The expression of the fos-CAT fusion genes was stimulated only two to three times by the fos inducer 12-0-tetradecanoyl phorbol-13-acetate. The fos enhancer does not appear to be tissue-specific.

Acetyltransferases↗
PubMed1985

Removal of a 67-base-pair sequence in the noncoding region of protooncogene fos converts it to a transforming gene.

Transformation of fibroblasts by protooncogene fos (c-fos) requires the linkage of viral long terminal repeat (LTR) sequences and interruption of 3'-noncoding sequences. We have identified an A + T-rich stretch of 67 nucleotides, located 627-693 base pairs downstream from the coding domain and 123-189 base pairs upstream from the putative poly(A) addition site, removal of which confers transforming activity to the c-fos gene. A novel regulation of the expression of the c-fos gene is proposed, which may be functional in vivo to prevent the gene from becoming an oncogene.

Animals↗