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Results for “Genes, Intracisternal A-Particle”

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PubMed1996

Malignant transformation induced by cytokine genes: a comparison of the abilities of germline and mutated interleukin 3 genes to transform hematopoietic cells by transcriptional and posttranscriptional mechanisms.

The effects of inheritance of germline (gIL3) and rearranged interleukin 3 (rIL3) genes on the factor dependency and tumorigenicity of a hematopoietic cell line were compared. The rIL3 gene arose after intracisternal type A particle transposition into the 3' untranslated region (UTR). The rlL3 gene efficiently transformed cells. In contrast, factor-independent cell lines were recovered only rarely from gIL3-transfected cells, and they fell into two categories. One class inherited more than one copy of the transgene and expressed moderate levels of lL-3, whereas the other group received one copy and expressed lower amounts of lL-3. Tumorigenicity was associated with the quantity of lL-3 expression because cells from the first class were malignant, whereas those from the latter set were not. To determine which portions of the rIL3 gene were responsible for cell transformation, chimeric constructs were made containing exchanged sections of the gIL3 and rIL3 genes. The transforming region was mapped to the 3' end of the rIL3 gene, and no point mutations in the promoter region were detected. RNA gel shift assays indicated that the transposition eliminated the ability of proteins to bind the 3'UTR. These results demonstrate that the mutation of the IL-3 3'UTR by intracisternal type A particle transposition results in: (a) the inability of proteins to bind the 3'UTR; (b) prolonged mRNA half life; (c) constitutive IL-3 expression; (d) cytokine independence; and (e) tumorigenicity. Inheritance of a gIL3 gene was not normally sufficient to abrogate cytokine dependency; however, rare tumorigenic cells were isolated, implicating the importance that deregulated cytokine expression can have upon malignant transformation.

Animals↗

PubMed1979

Intracisternal A-particles in genetically diabetic mice: identification in pancreas and induction in cultured beta cells.

Sucrose density gradient analysis of purified pancreatic homogenates from glycaemic C57BL/Ks diabetes (db/db) mice and their normoglycaemic controls have revealed the presence in the diabetics of increased Mg++-dependent RNA-directed DNA polymerase activity sedimenting with a density of approximately 1.21 g/cm3. Electron microscopy revealed that this fraction contained typical intracisternal A-particles. Purified cultures of pancreatic islet cells 4--7 day old postnatal "misty diabetic" mice and normal siblings were established and then maintained in Eagle's minimal essential medium without serum. Under these conditions, the presence of intracisternal A-particles in beta cells of both mutant and control genotypes was very rare. No change in numbers of intracisternal A-particles was seen after 2--4 days of incubation in Dulbecco's-modified minimal essential medium containing 5.5 mmol/l glucose. However, when the glucose concentration of Dulbecco's medium was elevated to 16.5 mmol/l, ultrastructural changes specific to the beta cell population occurred that were reminiscent of those alterations observed in situ. Intracisternal A-particles were commonly seen in cultured beta cells showing hypersecretion-stress morphology. Since equal numbers of intracisternal A-particles were present in cultured beta cells from normal and mutant mice, it was concluded that the db gene itself was not required for intracisternal A-particle expression. The cell culture results suggest that elevated intracisternal A-particle activity observed in vivo may be produced directly or indirectly by the ambient high blood glucose levels characteristic of this mutant.

Animals↗

PubMed1993

Suppressible and nonsuppressible autocrine mast cell tumors are distinguished by insertion of an endogenous retroviral element (IAP) into the interleukin 3 gene.

After v-H-ras expression, the interleukin 3 (IL-3)-dependent PB-3c mast cells progress in vivo to two different classes of IL-3 autocrine tumors. Class I tumors show a germline configuration of the IL-3 gene and represent more than 90% of tumors analyzed so far. Somatic cell fusion of class I tumor lines with the nontumorigenic parental PB-3c resulted in loss of oncogenic IL-3 expression by a posttranscriptional mechanism with concomitant tumor suppression. Class II tumors arise rarely and contain an insertion in one IL-3 allele. This alteration was linked to enhanced IL-3 gene transcription. For one tumor, the insertion was shown to be an endogenous retroviral element (intracisternal A-particle). Cell hybrids of class II tumors with PB-3c remained IL-3 independent, expressed IL-3, and formed tumors rapidly. These results suggest that the v-H-ras oncogene synergizes with a recessive and a dominant lesion in class I and II tumors, respectively, both of which lead to the autocrine production of IL-3.

Animals↗

PubMed1994

Constitutive expression of the putative transcription factor SCL associated with proviral insertion in the myeloid leukemic cell line WEHI-3BD-.

The murine myeloid leukemia WEHI-3B contains an intracisternal A-particle insertion in a growth factor gene (IL-3) and a homeobox gene (Hox 2.4). Southern blot analysis of the differentiation unresponsive subline WEHI-3BD- demonstrated a rearrangement of the SCL gene, a gene that encodes a protein of the helix-loop-helix class of transcription factors. Northern blot analysis demonstrated an abnormal SCL transcript in the WEHI-3BD- cells, although SCL expression was not detected in the parental cells. The rearrangement was cloned and confirmed as an insertion of an intracisternal A-particle in the 3' untranslated region of the SCL gene. Although SCL is implicated in up to 25% of human T-cell acute lymphoblastic leukemia, this is the first example of SCL involvement in a myeloid leukemia.

Animals↗

PubMed1990

Establishment of an interleukin-5-dependent subclone from an interleukin-3-dependent murine hemopoietic progenitor cell line, LyD9, and its malignant transformation by autocrine secretion of interleukin-5.

An interleukin-5 (IL-5)-dependent subclone, K-5, was established from an IL-3-dependent murine hemopoietic progenitor cell line by co-culturing with bone marrow stroma cells. K-5 cells were induced to differentiate into myeloid lineage cells by co-culturing with cloned PA6 stroma cells. By co-culturing with another cloned stroma cell (ST-2s10), K-5 cells gave rise to a factor-independent transformant cell line LT-5 which proliferated in an autocrine manner by secretion of IL-5 and produced tumors in nude mice. Molecular cloning of the IL-5 gene of LT-5 cells and the nucleotide sequencing of its 5' flanking region indicate that a transposition of an intracisternal A-particle (IAP) element to the 5' flanking region of the IL-5 gene is responsible for the constitutive expression of IL-5 mRNA of an aberrant size in LT-5 cells.

Animals↗

PubMed1991

Gene expression of an endogenous retrovirus-like element during murine development and aging.

We have measured intracisternal A-particle (IAP) RNA levels during development and aging in C57BL/6J mouse tissues to determine possible age-dependent changes in gene expression of these retrovirus-like sequences. Total RNA was isolated from tissues of embryonic and new born mice and mice ranging in age from 2 months to 32 months of age. RNA samples were either slot-blotted directly or fractionated on denaturing agarose gels and transferred to nylon membranes. Hybridization with cloned, 32P-labeled IAP sequences showed that both the mass amounts and the relative proportions of IAP transcripts varied between tissues and as a function of age. IAP gene products were higher in brain and kidney tissues than in liver and heart tissues. The relative proportion of transcripts increased in embryonic tissues until birth and following birth, was highest in neonatal or 2-month-old tissues. The adult levels of IAP-related RNAs did not change significantly from 6 to 24 months of age. However, 32-month-old tissues exhibited the lowest content of IAP transcripts, with the exception of heart tissue which did not change with age. A 5.4-kb RNA was the predominant IAP transcript in most samples, but each tissue had a characteristic size distribution of IAP-related transcripts. These results demonstrate that transcription of IAP genes continues throughout the life span of this mouse strain with tissue-specific and age-dependent regulation of expression.

Aging↗

PubMed1996

Frequent ectopic expression of a placenta-specific gene at high levels in BALB/c mouse mammary carcinomas.

A placenta-specific gene, MIPP, is transcriptionally regulated in BALB/c mice by a solo long terminal repeat (LTR) of an intracisternal A-particle (IAP), an endogenous retrotransposon. Expression of IAPs, which is also promoted by LTR sequences, is a frequent aberration in many mouse mammary tumors of BALB/c mice. Given that these retroelements and the placental gene have a common promoter, we hypothesized that the tumors also express the gene. Northern blot analysis and RT-PCR revealed high expression of the placenta-specific gene in BALB/c mouse mammary preneoplasias and carcinomas of diverse etiologies, but not in normal mammary gland from virgin, pregnant and lactating mice. The preneoplasias and tumors expressed two transcripts, one of which is apparently unique to the mammary lesions. The other transcript is the same as one expressed in placenta that is not promoted by the IAP LTR. Despite the parallel expression of the placental gene and IAPs in the mammary tissues, RT-PCR showed that LTR sequences are absent from tumor-associated MIPP transcripts. Southern analysis revealed no gross mutations of the MIPP gene in mammary preneoplasias and tumors. The ectopic expression of the placenta-specific gene in BALB/c mouse mammary preneoplasias and carcinomas raises the possibility that it acts as an oncogene.

Animals↗

PubMed1994

Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage.

The agouti gene normally confers the wild-type coat color of mice. Dominant mutations at the agouti locus result in a pleiotropic syndrome that is characterized by excessive amounts of yellow pigment in the coat, obesity, a non-insulin-dependent diabetic-like condition, and the propensity to form a variety of tumors. Here, we describe a new dominant mutation at the agouti locus in which an intracisternal A-particle (IAP) has integrated in an antisense orientation immediately 5' of the first coding exon of the gene. This mutation, which we have named Aiapy, results in the ectopic expression of the agouti gene through the utilization of a cryptic promoter within the IAP 5' long terminal repeat (LTR). The coat color of Aiapy/-mice ranges from solid yellow to a pigment pattern that is similar to wild type (pseudoagouti), and the expressivity of this mutant phenotype varies with parental inheritance. Those offspring with a yellow coat ectopically express agouti mRNA at high levels and exhibit marked obesity, whereas pseudoagouti mice express agouti mRNA at a very low level and their weights do not differ from wild-type littermates. Data are presented to show that the differential expressivity of the Aiapy allele is correlated with the methylation status of the inserted IAP 5' LTR. These data further support the hypothesis that in dominant yellow mutations at the agouti locus, it is the ubiquitous expression of the wild-type agouti coding sequence that is responsible for the yellow coat color, obesity, diabetes, and tumorigenesis.

Agouti Signaling Protein↗

PubMed1990

Submegabase clusters of unstable tandem repeats unique to the Tla region of mouse t haplotypes.

We describe here the identification and genomic organization of mouse t haplotype-specific elements (TSEs) 7.8 and 5.8 kb in length. The TSEs exist as submegabase-long clusters of tandem repeats localized in the Tla region of the major histocompatibility complex of all t haplotype chromosomes examined. In contrast, no such clusters were detected among 12 inbred strains of Mus musculus and other Mus species; thus, clusters of TSEs represent the first absolutely qualitative difference between t haplotypes and wild-type chromosomes. Pulsed field gel electrophoresis shows that the number of clusters, and the number of repeats in each cluster are extremely variable. Dramatic quantitative differences of TSEs uniquely distinguish every independent t haplotype from any other. The complete nucleotide sequence of one 7.8-kb TSE reveals significant homology to the ETn (a major transcript in the early embryo of the mouse), and some homologies to intracisternal A-particles and the mammary tumor virus env gene. Apart from the diagnostic relevance to t haplotypes, evolutionary and functional significances are discussed with respect to chromosome structure and genetic recombination.

Animals↗

PubMed1990

Isolation of genes highly expressed in early and late stages of Friend virus-induced erythroleukemia in mice.

We isolated two genes that are highly expressed in Friend erythroleukemia. The first one, expressed at an extremely high level in a late-stage tumorigenic cell line F5-5, was found to be a species of intracisternal A-particle. Most of those genomes in F5-5 DNA were not amplified nor rearranged compared with those in the normal cell DNA, suggesting transcriptional activation. Another late-stage cell line T3K showed similar results. The second gene, highly expressed in early-stage cells but weaker in late-stage cells, was identified as one of the heme-synthesizing enzymes, uroporphyrinogen decarboxylase. Usefulness of these two genes for the analysis of erythroid transformation and differentiation will be discussed.

Animals↗

PubMed1987

Nearly identical members of the heterogeneous IAP gene family are expressed in thymus of different mouse strains.

Poly(A)RNAs prepared from the thymuses of C57BL/6J and DBA/2J mice were used to construct cDNA libraries in the bacterial expression vector lambda gt11. The libraries were scanned first for protein production with polyvalent antiserum prepared against the 73kDa gag protein of mouse intracisternal A-particles (IAP). Reactive plaques were crossed-screened by hybridization with an IAP-specific DNA probe. Two IAP-specific protein-producing plaques were obtained from the C57BL/6 library and 4 from the DBA/2 library. One C57BL/6 cDNA clone (B12) and two DBA cDNA clones (D8 and D20) were sequenced in their entirety. Clones B12 and D8 were remarkably similar, particularly when compared to the 6 other IAP elements that have been sequenced thus far. We discuss the evidence which leads us to suggest that these clones may be derived from allelic IAP elements expressed in mouse thymus.

Alleles↗

PubMed1983

Methylation and rearrangement of mouse intracisternal a particle genes in development, aging, and myeloma.

Sequences of DNA that hybridize on Southern blots with cloned intracisternal A-particle (IAP) sequences have been examined in genomic DNAs of neonatal mice, livers of adult mice (3, 6, 12, 18, 24, and 26 months old), and the solid myeloma tumor MOPC-315. The isoschizomers HpaII (CCGG or mCCGG) and MspI (CCGG or CmCGG) were used to assess methylation. All the DNAs produced a major 0.5-kilobase MspI fragment that hybridizes with IAP probe. Only the myeloma DNA, and to a much lesser degree DNA from senescent mouse liver, produced this fragment in HpaII digest; the other DNAs all had IAP sequences resistant to HpaII digestion. These sequences thus become fully methylated to CmCGG early and remain so in adult life, except in the myeloma cells that are expressing the IAP genes. An increase in MspI-sensitive sites in IAP gene-containing DNA was observed in aging mice. The probe used to assess methylation, a 0.8-kilobase fragment produced by BamHI-HindIII double digestion, is common to several cloned IAP genes and is part of a region of DNA which is conserved in genomes of all mouse tissues. The probe hybridized to 1.5- and 1.4-kilobase doublet bands produced by BamHI, HindIII, and EcoRI triple digestions of neonatal DNA. These two bands were found in neonatal livers of Swiss Webster, BALB/c, and C57BL/6J mouse strains, showed less in adult liver, and were barely detectable in senescent livers from C57BL/6J mice.

Aging↗

PubMed1996

[Analysis of a novel gene expressed in apoptotic T-cell hybridoma treated with dexamethasone].

Developmentally and physiologically controlled cell deaths are called programmed cell death (PCD), and distinguished from accidental cell death while apoptosis is defined morphologically as a certain type of cell death (i.e. chromatin condensation, DNA fragmentation, organella compaction, and blebing of cell and nuclear membranes). Apoptosis is often associated with PCD. Most of cells undergoing PCD have been shown to require de novo synthesis of mRNA and protein. A number of genes have been reported to be expressed in apoptotic cells. In the immune system programmed cell death plays an important role in negative selection of immature T cells. Situations that result in programmed cell death include the withdrawal of cytokine from cultures of cytokine dependent cells, lysis of target cells by cytotoxic T cells, and activation of T cells. In T cells, another well described means of inducing apoptosis is an exposure to glucocorticoids. We cloned a novel gene expressed in apoptotic 2B4. 11 mouse T-cell hybridoma treated with steroid. This gene was not detected in vivo, but was so in mouse thymocytes and splenocytes cultured with dexamethasone and IgM stimulated mouse preB cell line WEHI-231. Thirty-six amino acids, position 2-37, has a 37% homology to mouse intracisternal A-particle gag p27 protein.

Amino Acid Sequence↗

PubMed1995

Structure and chromosomal localization of the mouse oncomodulin gene.

The rat gene encoding oncomodulin (OM), a small calcium-binding protein, is under the control of a solo LTR derived from an endogenous intracisternal A-particle. The latter sequence is the only OM promoter analyzed so far. In order to study cell type-specific OM expression in a species lacking LTR sequences in the OM locus, we initially synthesized an OM cDNA from mouse placenta. By sequencing, we found a 137-bp-long 5'leader region that differed markedly from its rat counterpart but had high similarity to several mouse genomic sequences. Primers specific to this sequence in addition with primers specific for an exon 2/intron 2 sequence were used to screen a mouse ES cell line genomic P1 library. One positive clone contained the whole OM gene, including intron 1 of 25kb and a 5' flanking region of 27 kb lacking an LTR. The region upstream of exon 1 contains no TATA or CCAAT boxes but has a homopurine/homopyrimidine stretch of 102 bp as well as a (CA)22 repeat. The latter sequence is polymorphic and was therefore, used to map the OM gene to the distal end of the long arm of mouse Chromosome (Chr) 5 by interspecific backcross analysis. Additionally we localized the OM gene by in situ hybridization to the region G1-3 on Chr 5, confirming the genetic linkage results. Finally, the OM gene was found to be structurally conserved and to exist in a single copy in mammals.

Amino Acid Sequence↗

PubMed1993

Characterization of murine middle repetitive DNA.

We have characterized four sequences from a small library containing a subset of the repetitive families of the mouse. Each clone has a repetition frequency of less than 1,100 copies per genome and each clone represents a unique family of middle repetitive DNA. One clone (pMR111) shares homology with mouse intracisternal A-particle (IAP) elements, a second clone (pMR89) has partial homology with a sequence in the 3' untranslated region of the human fibulin gene, while two clones (pMR6, pMR66) are new that have no homology to any reported DNA sequence. Each clone hybridizes to one or two discrete RNA transcripts from one or more tissues of the mouse. Clone pMR66 detected restriction fragment length polymorphisms (RFLPs) at three loci in genomic mouse DNA, defining loci at the distal end of chromosome 5 and the proximal end of chromosome 7. The third locus is unmapped. This study demonstrates that cloned repeats from a repetitive DNA library are a potential source of genetic markers.

Amino Acid Sequence↗

PubMed1986

Nucleotide sequence of human endogenous retrovirus genome related to the mouse mammary tumor virus genome.

We determined the complete nucleotide sequence of the human endogenous retrovirus genome HERV-K10 isolated as the sequence homologous to the Syrian hamster intracisternal A-particle (type A retrovirus) genome. HERV-K10 is 9,179 base pairs long with long terminal repeats of 968 base pairs at both ends; a sequence 290 base pairs long, however, was found to be deleted. It was concluded that a composite genome having the 290-base-pair fragment is the prototype HERV-K provirus gag (666 codons), protease (334 codons), pol (937 codons), and env (618 codons) genes. The size of the protease gene product of HERV-K is essentially the same as that of A- and D-type oncoviruses but nearly twice that of other retroviruses. A comparison of the deduced amino acid sequences encoded by the pol region showed HERV-K to be closely related to types A and D retroviruses and even more so to type B retrovirus. It was noted that the env gene product of HERV-K structurally resembles the mouse mammary tumor virus (type B retrovirus) env protein, and the possible expression of the HERV-K env gene in human breast cancer cells is discussed.

Amino Acid Sequence↗

PubMed1979

Tumorigenicity and intracisternal A-particle expression of hybrids between murine myeloma and lymphocytes.

Hybrids of BALB/c lymphocytes and a murine myeloma, a tumor that expresses intracisternal A-particles, were obtained with polyethylene glycol as the fusogen. The karyotype, tumorigenicity, and A-particle expression of the hybrid clones were assessed. All the hybrid clones analyzed were tumorigenic and expressed intracisternal A-particles even when they were the result of a fusion event between two lymphocytes and one myeloma cell in which no loss of chromosomes was detected. The tumors that developed following inoculation of hybrid cells into BALB/c mice (1 x 10(6) cells/mouse) were karyotypically identical to the inoculated cells. It appears that the two myeloma cell phenotypic traits analyzed (tumorigenicity and A-particle expression) are dominant.

Animals↗

PubMed2025

DNA methylation at retrotransposons protects the germline by preventing NRF1-mediated activation.

Silencing evolutionary young retrotransposons by cytosine DNA methylation is essential for spermatogenesis, as failure to methylate their promoters leads to reactivation, meiotic failure, and infertility. How retrotransposons reactivate in the absence of DNA methylation is poorly understood. We show that upon defective DNA methylation, distinct retrotransposon families display unique expression patterns and chromatin landscapes during mouse spermatogenesis. We find that their reactivation in meiotic spermatocytes correlates with the loss of bivalent H3K4me3-H3K27me3 chromatin marks. Through proteomics and chromatin profiling, we identify NRF1 as a DNA methylation-sensitive transcription factor that transactivates unmethylated retrotransposons. Conditional germline knockout of Nrf1 in the absence of DNA methylation rescues the silencing of the most mutagenic retrotransposon in mice, namely Intracisternal A-particle or IAP. Our findings reveal that chromatin modifications together with a DNA methylation-sensitive transcription factor regulate retrotransposon expression in the absence of DNA methylation in spermatogenesis, revealing a mechanism by which retrotransposons proliferate in the germline after evading DNA methylation-based silencing.

Animals↗