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PubMed1996

Upregulation of the Drosophila 1731 retrotransposon long-terminal repeat by UV-B irradiation requires a short sequence in the U3 region.

A 1731 is a Drosophila melanogaster retrotransposon, the transcripts of which decrease in Drosophila cells after treatment by the 20-hydroxyecdysone (20-OH), the steroid-molting hormone of insects. In order to analyze the regulation of the long terminal repeat (LTR) directed transcription by UV-B, S2 Drosophila cells were transfected with various chimeric constructs carrying the LTR of 1731 linked to the bacterial chloramphenicol acetyltransferase (CAT) reporter gene and then subjected to UV-B irradiation. The results demonstrated that the 1731 LTR is activated by UV-B irradiation in a dose- and time-dependent manner. Using constructions expressing the reporter gene under the control of either the entire or deleted LTRs of 1731, we established that a sequence located in the U3 region was required for the retrotransposon to respond to UV-B. The cis-acting element is identical to the binding sequence of the dorsal transcription factors. In addition, the S2 Drosophila cell produced extracellular factor(s) in response to UV-B irradiation which activated the 1731 LTR in nonirradiated cells. This factor(s) was detected when responding cells were cocultured with inducing cells and when conditioned medium from irradiated cultures was added to the cell cultures.

Animals↗
PubMed2006

Sequence polymorphisms in the long terminal repeat of bovine leukemia virus: evidence for selection pressures in regulatory sequences.

Bovine leukemia virus (BLV) is an oncogenic virus widespread in cattle. It belongs to the genus Deltaretrovirus of the family Retroviridae along with human and simian T-lymphotropic viruses. The BLV transcriptional promoter is located in the proviral 5' long terminal repeat (LTR), composed of U3, R, and U5 regions. BLV LTR contains multiple cis-acting elements important for promoter activity, a short coding sequence (encoding the NH(2) terminus of the G4 regulatory protein), and non-regulatory/non-coding regions. Variation in coding sequences of BLV structural proteins has been studied extensively, but little work has been done on sequence variability of non-coding regions, mostly located in LTR. Here, we report the first study on the natural diversity of the BLV LTR, using viral isolates from 52 cattle in several different areas worldwide. Nucleotide variations from the consensus sequence were observed in most isolates and clustered phylogenetically, corresponding to the geographic distribution of donor cattle. Overall, regulatory regions were significantly more conserved than non-regulatory regions in the BLV LTR, as well as in LTR sub-regions (U3, R, and U5). Evidence of selection pressures in BLV LTR suggests that selection occurs not only in coding sequences, but may also involve regulatory sequences.

5' Untranslated Regions↗
PubMed2000

The Rous sarcoma virus long terminal repeat promoter is regulated by TFII-I.

Many viral genes contain core promoters with two basal control elements, the TATA box and the pyrimidine-rich initiator (Inr). However, the molecular mechanisms involved in transcription initiation from composite core promoters (TATA(+) Inr(+)) containing Inr elements are unclear. The Rous sarcoma virus (RSV) long terminal repeat (LTR) contains a transcriptionally potent enhancer and core promoter composed of a TATA box and an Inr-like sequence, termed the transcription start site core (TSSC). Previously we demonstrated that the TSSC binds the multifunctional Inr-binding protein YY1. Here we present evidence that the TSSC also binds the multifunctional transcription factor TFII-I and that both TFII-I and YY1 are required for RSV LTR transcriptional activity. Gel shift assays using anti-TFII-I antibody show that TFII-I is present in a protein complex that specifically binds to the TSSC. Mutations in the TSSC that reduce TFII-I binding also reduce RSV LTR enhancer and promoter activity. Transient-transfection assays demonstrate that TFII-I transactivates the RSV LTR from ca. fourfold (basal) to ca. sevenfold (enhanced) in both human and natural host cell lines. Importantly, the activity of the TSSC element can be attributed to the binding activity of TFII-I and the YY1 protein, since mutation of each of these binding sites within the TSSC element abolishes all viral expression as demonstrated by transient-transfection assays. Taken together, these data demonstrate that expression of RSV viral mRNA is dependent on both TFII-I and YY1.

Animals↗
PubMed2004

Cell cycle arrest in G2 induces human immunodeficiency virus type 1 transcriptional activation through histone acetylation and recruitment of CBP, NF-kappaB, and c-Jun to the long terminal repeat promoter.

In human immunodeficiency virus type 1 (HIV-1)-infected cells, a cell cycle arrest in G(2) increases viral expression and may represent a strategy for the virus to optimize its expression. In latently infected cells, balance between viral silencing and reactivation relies on the nucleosomal organization of the integrated long terminal repeat (LTR). It is shown here that nucleosome nuc-1, which is located downstream of the TATA box, is specifically modified when latently infected cells are arrested in G(2) by chemical inducers. Notably, histones H3 and H4 are hyperacetylated, and this modification is associated with an increased LTR-driven transcription. nuc-1 hyperacetylation is also associated with the recruitment of histone acetyltransferase CBP and transcription factors NF-kappaB and c-Jun. NF-kappaB and/or c-Jun binding to the LTR in G(2)-arrested cells appears to be required for CBP recruitment as well as for nuc-1 remodeling and viral reactivation.

Acetylation↗
PubMed1995

Rejection antigen peptides on BALB/c RL male 1 leukemia recognized by cytotoxic T lymphocytes: derivation from the normally untranslated 5' region of the c-akt proto-oncogene activated by long terminal repeat.

Tumor antigen peptides on BALB/c leukemia RL male 1 that were recognized by cytotoxic T lymphocytes were shown to be derived from a normally untranslated region of the akt proto-oncogene (Uenaka, A. et al., J. Exp. Med., 180: 1599, 1994). We show here that the murine leukemia virus (MuLV) long terminal repeat (LTR) was inserted directly into the exon of c-akt in RL male 1 leukemia and that transcription started from the cap site of the LTR. Translation appeared to start from the ATG codon created in the six nucleotides of unknown origin, which were inserted into the LTR/akt junction. The deduced molecular size is approximately M(r) 59,000 due to the addition of 33 amino acid residues to the normally expressed c-AKT protein. Western blot analysis demonstrated the presence of M(r) 59,000 molecules in an RL male 1 lysate, and their expression at about ten times the level of normal AKT molecules of M(r) 56,000, which is consistent with the increased expression of akt mRNA demonstrated by Northern blot analysis. The findings show that the molecular alteration of AKT protein by insertion of MuLV LTR is the mechanism for creating rejection antigen peptides derived from the untranslated region of akt.

Amino Acid Sequence↗
PubMed1989

Sequences in the visna virus long terminal repeat that control transcriptional activity and respond to viral trans-activation: involvement of AP-1 sites in basal activity and trans-activation.

Visna virus is a pathogenic lentivirus of sheep whose gene expression is developmentally regulated in cells of the monocyte-macrophage lineage. Gene expression directed by the visna virus long terminal repeat (LTR) is increased in infected cells by a virus-encoded trans-acting protein. trans-Activation is mediated in part by increases in the steady-state level of mRNA. Deletion and linker-scanner mutants were constructed to locate sequences in the LTR that regulate transcription and are responsive to viral trans-activation. The activities of these mutants were tested by using them to drive transcription of the bacterial gene for chloramphenicol acetyltransferase in transient expression assays. Three regions located between-140 and the cap site were found to be important for basal transcriptional activity, and the importance of each region was found to be dependent on the cell type. Sequences responsive to viral trans-activation were found to be the same sequences required for basal transcriptional activity. The visna virus LTR contains six sequences that are homologous to the recognition site for cellular transcriptional factor AP-1 and a single sequence homologous to the recognition site for transcriptional factor AP-4. Both of these classes of binding sites appear to be important for regulating the basal level of transcription of visna virus. The AP-1-binding site most proximal to the TATA box was found to be one target for viral trans-activation. The visna virus promoter was found to be activated by serum; this serum response has also been mapped to the AP-1-related sequences in the LTR.

Base Sequence↗
PubMed1987

The bovine leukemia virus X region encodes a trans-activator of its long terminal repeat.

We constructed a fusion plasmid, pMX-I, by which the major open reading frame, X-I, of the bovine leukemia virus (BLV) X gene was expressed under control of the mouse metallothionein promoter. pMX-I was cotransfected into CV1 monkey kidney cells together with another construct containing the BLV long terminal repeat (LTR) linked to the chloramphenicol acetyltransferase (CAT) structural gene. The result of assay of CAT synthesis suggests that the X-I product functions as a trans-acting activation factor of the BLV LTR.

Acetyltransferases↗
PubMed1988

Size and genetic composition of long terminal repeat sequences in the mouse intracisternal A-particle gene 81.

The intracisternal A-particle (IAP) genome is a retrovirus-like gene family. Over 1000 copies of IAP genes are dispersed throughout the mouse genome. The purpose of this study was to determine the nucleotide sequence of both ends of the long terminal repeat (LTR) units which bind the IAP gene 81. The results obtained showed that, whereas the structural domain and several genomic characteristics of the IAP 81 LTR units and other LTR structures of a given IAP gene were almost identical, the nucleotide sequences of these LTR units associated with different IAP gene were sometimes very different from each other. In the comparisons of different LTR structures, the transcriptional signals for promotion, initiation, polyadenylation and termination as well as several characteristic sequences of the Z-DNA region, enhancer core sequence and glucocorticoid-responsive element were all found to be present in IAP 81 LTRs. The possible roles of the primary nucleotide sequence of an LTR structure are discussed.

Animals↗
PubMed1989

Indirect binding of human T-cell leukemia virus type I tax1 to a responsive element in the viral long terminal repeat.

Several laboratories have demonstrated that tandem copies of the human T-cell leukemia virus type I 21-base-pair (bp) repeat cloned upstream of either a homologous or heterologous promoter increase transcription in the presence of tax1 protein. In this report, we provide evidence for a second tax1-responsive sequence in the viral long terminal repeat. Analysis of human T-cell leukemia virus type I promoter deletion mutants and plasmids containing cloned oligonucleotide motifs demonstrated that this 47-bp sequence, located between -117 and -163, confers responsiveness to tax1. We further demonstrated that proteins present in HeLa nuclear extracts bind specifically to this tax1-responsive sequence. Mutants that affected in vivo activity also decreased in vitro binding. Using an in vitro binding assay, we demonstrated that tax1 interacts indirectly with the 47-bp sequence, most likely through protein-protein interaction. Thus, while tax1 does not bind directly to DNA to enhance transcription, it may influence sequence-specific responses by interacting with the primary DNA-protein complex.

Animals↗
PubMed1997

The feline leukemia virus long terminal repeat contains a potent genetic determinant of T-cell lymphomagenicity.

Feline leukemia virus (FeLV) is an important pathogen of domestic cats. The most common type of malignancy associated with FeLV is T-cell lymphoma. SL3-3 (SL3) is a potent T-cell lymphomagenic murine leukemia virus. Transcriptional enhancer sequences within the long terminal repeats (LTRs) of SL3 and other murine retroviruses are crucial genetic determinants of the pathogenicities of these viruses. The LTR enhancer sequences of FeLV contain identical binding sites for some of the transcription factors that are known to affect the lymphomagenicity of SL3. To test whether the FeLV LTR contains a genetic determinant of lymphomagenicity, a recombinant virus that contained the U3 region of a naturally occurring FeLV isolate, LC-FeLV, linked to the remainder of the genome of SL3 was generated. When inoculated into mice, the recombinant virus induced T-cell lymphomas nearly as quickly as SL3. Moreover, the U3 sequences of LC-FeLV were found to have about half as much transcriptional activity in T lymphocytes as the corresponding sequences of SL3. This level of activity was severalfold higher than that of the LTR of weakly leukemogenic Akv virus. Thus, the FeLV LTR contains a potent genetic determinant of T-cell lymphomagenicity. Presumably, it is adapted to be recognized by transcription factors present in T cells of cats, and this yields a relatively high level of transcription that allows the enhancer to drive the requisite steps in the process of lymphomagenesis.

3T3 Cells↗
PubMed1989

Regulation of the visna virus long terminal repeat in macrophages involves cellular factors that bind sequences containing AP-1 sites.

Visna virus gene expression is highly restricted in monocytes but is induced by monocyte-macrophage differentiation in vivo. Deletion and linker-scanning mutants, gel shift assays, and DNase I footprinting were used to identify sequences in the visna virus long terminal repeat involved in the developmental regulation of gene expression in the U937 monocytic cell line. We found that an AP-1 and an AP-4 binding site were critical for basal activity and that the AP-1 site was required for phorbol ester-inducible gene expression. These results suggest that cellular factors that interact with AP-1 sites are involved in the developmental regulation of visna virus gene expression in macrophages.

Base Sequence↗
PubMed1984

Characterization of a solitary long terminal repeat of avian endogenous virus origin.

A recombinant lambda phage library constructed with a partial EcoR1 digest of DNA from a normal RPRL line 15B chicken was screened using 32P-labeled plasmid containing Rous-associated virus (pRAV-2). Nucleotide sequence analyses of a fragment of one subclone revealed the presence of a solitary long terminal repeat (LTR) that is similar to the LTRs of avian endogenous retroviruses ev1 and ev2. This LTR is flanked by unique 6 bp direct repeats characteristic of the target site for duplication of avian leukosis viruses.

Animals↗
PubMed1989

Functional analysis of the long terminal repeats of Drosophila 1731 retrotransposon: promoter function and steroid regulation.

1731 is a Drosophila retrotransposon whose transcripts decrease in Drosophila cells after treatment by the steroid hormone 20-hydroxyecdysone (20-OH). Several constructions have been made where the bacterial chloramphenicol acetyltransferase (CAT) gene is put under the control of either the 5' or the 3' long terminal repeats (LTRs) of 1731. CAT activity assays in transfected Drosophila cells show that either the 5' or the 3'LTR constitutes a unidirectional promoter. Analysis of partially deleted LTR suggests the presence of so-called silencer and activator regions in these LTRs. Moreover, the first 260 bp of the LTR are sufficient to provoke 20-OH inhibition whereas the first 58 bp are necessary for hormonal responsiveness. These 58 bp contain sequences showing similarities with the targets of trans-acting factors such as Octal-c and NFkB.

Animals↗
PubMed1994

Inhibition of human T cell leukaemia virus type I long terminal repeat expression by DNA methylation: implications for latency.

Human T cell leukaemia virus type I (HTLV-I) provirus DNA was found to be methylated in patients with adult T cell leukaemia. We have therefore examined the possibility that DNA methylation might contribute to HTLV-I latency. In vitro methylation of HTLV-I long terminal repeat (LTR)-chloramphenicol acetyltransferase or LTR-Luciferase constructs at eight HpaII sites, a subset of the eukaryotic methylation site CpG, resulted in a three- to fourfold inhibition of transcription in transfected cells. Inhibition of transcription by methylation of all CpG methylation sites using SssI methylase was much more pronounced (50- to 80-fold). As partial methylation of the LTR showed, methylation of the promoter region was responsible for most of the effect. Whereas cellular stimulation by a combination of phorbol 12-myristate 13-acetate and Tax was able to reverse the HpaII methylation effect, the inhibition by SssI methylation was not suppressible under these conditions. The results are in line with a possible function of DNA methylation in HTLV-I latency.

Adult↗
PubMed1988

Activation of the human immunodeficiency virus long terminal repeat by herpes simplex virus type 1 is associated with induction of a nuclear factor that binds to the NF-kappa B/core enhancer sequence.

It has been previously shown that herpes simplex virus type 1 (HSV-1) infection of HeLa cells results in augmentation of gene expression directed by the human immunodeficiency virus (HIV) long terminal repeat (LTR). This effect is presumably mediated by protein interactions with the LTR. We have used two different assays of DNA-protein interactions to study the HSV-induced activation of the HIV LTR. Activation of the HIV LTR is associated with increased protein binding to LTR sequences in a region including the NF-kappa B/core enhancer and the Sp1 binding sequences as monitored by an exonuclease protection assay. Gel retardation assays demonstrated that HSV-1 infection resulted in the induction of a nuclear factor(s) that binds to the NF-kappa B/core enhancer sequence. In addition to the activation of the HIV LTR, HSV induction of NF-kappa B activity may be important for the regulation of HSV gene expression during a herpesvirus infection.

Base Sequence↗
PubMed1990

Differences in the basal activity of the long terminal repeat determine different replicative capacities of two closely related human immunodeficiency virus type 1 isolates.

Two human immunodeficiency virus type 1 (HIV-1) variants derived from a single parental isolate were found to differ substantially in their ability to replicate in CD4-positive cells. Using transient chloramphenicol acetyltransferase expression assays, we show that the long terminal repeat (LTR) of the better-replicating virus has significantly higher capacity than that of the companion virus to direct gene expression in T cells. Sequence data and site-specific mutagenesis experiments demonstrate that the higher LTR activity of the better-replicating HIV-1 is due to a combined effect of two mutations: (i) a point mutation in position -94 (relative to the transcriptional start site), which is located between the two subunits of the HIV-1 enhancer, and (ii) a duplication of 24 base pairs in positions -128 to -151, which was not previously known to be involved in any regulatory function. The presence of these mutations increases the basal level of the LTR-driven gene expression and does not influence the degree of induction caused by the viral tat gene product or by cell activation. Reciprocal exchange of LTRs between the respective viral DNAs results in a change of a recombinant virus replication pattern consistent with the activity of the particular LTR. These experiments suggest that the HIV-1 LTR is one of the sites which determines the functional heterogeneity of HIV-1.

Base Sequence↗
PubMed1993

Mouse mammary tumor virus with rearranged long terminal repeats causes murine lymphomas.

Mouse mammary tumor virus (MMTV) is a slowly transforming retrovirus associated primarily with the induction of mammary tumors. It is widely accepted that T-cell lymphomas of various mouse strains are associated with extra proviruses of MMTV. These extra proviruses showed site-specific rearrangements in the U3 region of long terminal repeats (LTRs), consisting of about 400 nucleotide deletions and occasional substitution resulting in unique tandem repeats. However, the question of whether these mutant MMTVs cause lymphomas has not been experimentally resolved. Here we present distinct evidence that they do. We constructed chimeric MMTVs by replacing the LTR of the recently constructed pathogenic MMTV provirus clone with rearranged LTRs of MMTV proviruses obtained from two DBA/2 mouse lymphoma cell lines, MLA and DL-8, and inoculated them into BALB/c mice. These mice developed lymphomas, but no mammary tumors, 4 to 11 months postinoculation, whereas the original pathogenic MMTV clone alone induced mammary tumors. These results showed that the tissue specificity of MMTV tumorigenesis is determined by the LTR structures.

Animals↗
PubMed2004

Overlapping CRE and E box motifs in the enhancer sequences of the bovine leukemia virus 5' long terminal repeat are critical for basal and acetylation-dependent transcriptional activity of the viral promoter: implications for viral latency.

Bovine leukemia virus (BLV) infection is characterized by viral latency in a large proportion of cells containing an integrated provirus. In this study, we postulated that mechanisms directing the recruitment of deacetylases to the BLV 5' long terminal repeat (LTR) could explain the transcriptional repression of viral expression in vivo. Accordingly, we showed that BLV promoter activity was induced by several deacetylase inhibitors (such as trichostatin A [TSA]) in the context of episomal LTR constructs and in the context of an integrated BLV provirus. Moreover, treatment of BLV-infected cells with TSA increased H4 acetylation at the viral promoter, showing a close correlation between the level of histone acetylation and transcriptional activation of the BLV LTR. Among the known cis-regulatory DNA elements located in the 5' LTR, three E box motifs overlapping cyclic AMP responsive elements (CREs) in U3 were shown to be involved in transcriptional repression of BLV basal gene expression. Importantly, the combined mutations of these three E box motifs markedly reduced the inducibility of the BLV promoter by TSA. E boxes are susceptible to recognition by transcriptional repressors such as Max-Mad-mSin3 complexes that repress transcription by recruiting deacetylases. However, our in vitro binding studies failed to reveal the presence of Mad-Max proteins in the BLV LTR E box-specific complexes. Remarkably, TSA increased the occupancy of the CREs by CREB/ATF. Therefore, we postulated that the E box-specific complexes exerted their negative cooperative effect on BLV transcription by steric hindrance with the activators CREB/ATF and/or their transcriptional coactivators possessing acetyltransferase activities. Our results thus suggest that the overlapping CRE and E box elements in the BLV LTR were selected during evolution as a novel strategy for BLV to allow better silencing of viral transcription and to escape from the host immune response.

5' Untranslated Regions↗