Activation of an oncogenic microRNA cistron by provirus integration

The Gross passage A murine leukemia virus (MuLV) induced T-cell leukemia of clonal (or oligoclonal) origin in inoculated mice. To study the role of the integrated proviruses in these tumor cells, we cloned several newly integrated proviruses (with their flanking cellular sequences) from a single tumor in procaryotic vectors. With each of the five clones obtained, a probe was prepared from the cellular sequences flanking the provirus. With one such probe (SS8), we screened several Gross passage A MuLV-induced SIM.S mouse tumor DNAs and found that, in 11 of 40 tumors, a provirus was integrated into a common region designated Gin-1. A 26-kilobase-pair sequence of Gin-1 was cloned from two lambda libraries, and a restriction map was derived. All proviruses were integrated as a cluster in the same orientation within a 5-kilobase-pair region of Gin-1, and most of them had a recombinant structure of the mink cell focus-forming virus type. The frequency of Gin-1 occupancy by provirus was much lower in thymoma induced by other strains of MuLV in other mouse strains. Using somatic-cell hybrid DNAs, we mapped Gin-1 on mouse chromosome 19. Gin-1 was not homologous to 16 known oncogenes and was distinct from the other common regions for provirus integration previously described. Therefore, Gin-1 appears to represent a new common provirus integration region. The integration of a provirus within Gin-1 might be an important event leading to T-cell transformation, and the Gin-1 region might harbor sequences which are involved in tumor development.

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The Gfi-1B Proto-Oncoprotein Repressesp21WAF1 and Inhibits Myeloid Cell Differentiation

Molecular and Cellular Biology ◽

10.1128/mcb.18.5.2462 ◽

1998 ◽

Vol 18 (5) ◽

pp. 2462-2473 ◽

Cited By ~ 81

Author(s):

Betty Tong ◽

H. Leighton Grimes ◽

Tong-Yuan Yang ◽

Susan E. Bear ◽

Zhihai Qin ◽

...

Keyword(s):

Zinc Finger Protein ◽

Kinase Inhibitor ◽

Interleukin 2 ◽

Transcriptional Repressor ◽

Myeloid Cell ◽

Cyclin Dependent Kinase ◽

Coordinate Regulation ◽

Cyclin Dependent Kinase Inhibitor ◽

Finger Protein ◽

Provirus Integration

ABSTRACT Gfi-1 is a cellular proto-oncogene that was identified as a target of provirus integration in T-cell lymphoma lines selected for interleukin-2 (IL-2) independence in culture and in primary retrovirus-induced lymphomas. Gfi-1 encodes a zinc finger protein that functions as a transcriptional repressor. Here we show that Gfi-1B, a Gfi-1 related gene expressed in bone marrow and spleen, also encodes a transcriptional repressor. IL-6-induced G1 arrest and differentiation of the myelomonocytic cell line M1 were linked to the downregulation of Gfi-1B and the parallel induction of the cyclin-dependent kinase inhibitor p21 WAF1 . Experiments addressing the potential mechanism of the apparent coordinate regulation of these genes revealed that Gfi-1B represses p21WAF1 directly by binding to a high-affinity site at −1518 to −1530 in thep21WAF1 promoter. Forced expression ofGfi-1B, but not of Gfi-1B deletion mutants lacking the repressor domain, blocked the IL-6-mediated induction of p21 WAF1 and inhibited G1 arrest and differentiation. We conclude that Gfi-1B is a direct repressor of thep21WAF1 promoter, the first such repressor identified to date, and that sustained expression of Gfi-1B blocks IL-6-induced G1 arrest and differentiation of M1 cells perhaps because it prevents p21 WAF1 induction by IL-6.

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ICTV Virus Taxonomy Profile: Retroviridae 2021

Journal of General Virology ◽

10.1099/jgv.0.001712 ◽

2021 ◽

Vol 102 (12) ◽

Author(s):

John Coffin ◽

Jonas Blomberg ◽

Hung Fan ◽

Robert Gifford ◽

Theodora Hatziioannou ◽

...

Keyword(s):

Host Cell ◽

Reverse Transcription ◽

Viral Genome ◽

Inner Core ◽

Endogenous Retrovirus ◽

International Committee ◽

Virus Taxonomy ◽

The Family ◽

Vertebrate Hosts ◽

Provirus Integration

Viruses in the family Retroviridae are found in a wide variety of vertebrate hosts. Enveloped virions are 80–100 nm in diameter with an inner core containing the viral genome and replicative enzymes. Core morphology is often characteristic for viruses within the same genus. Replication involves reverse transcription and integration into host cell DNA, resulting in a provirus. Integration into germline cells can result in a heritable provirus known as an endogenous retrovirus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Retroviridae, which is available at ictv.global/report/retroviridae.

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CD8+ cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration

Microbiology ◽

10.1099/0022-1317-81-5-1261 ◽

2000 ◽

Vol 81 (5) ◽

pp. 1261-1264 ◽

Cited By ~ 34

Author(s):

Carl E. Mackewicz ◽

Bruce K. Patterson ◽

Sandra A. Lee ◽

Jay A. Levy

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Interleukin 2 ◽

Viral Rna ◽

Hiv Replication ◽

Immunodeficiency Virus ◽

Cd8 Cell ◽

Provirus Integration ◽

Replicative Cycle

CD8+ T cells from human immunodeficiency virus (HIV)-infected individuals can suppress HIV replication in CD4+ cells by a noncytotoxic mechanism that inhibits the expression of viral RNA. The present study examined whether other step(s) in the virus replicative cycle could be affected by the CD8+ cells. Culturing HIV-infected CD4+ T cells with antiviral CD8+ T cells did not significantly reduce the amounts of (i) early HIV DNA reverse transcripts (detected by LTR-U3/R), (ii) total nuclear HIV gag DNA, or (iii) integrated proviral DNA. However, exposure to the CD8+ T cells did cause a reduction in the amount of multiply spliced tat and full-length gag mRNA expressed by the infected CD4+ T cells, confirming previous observations. The levels of glyceraldehyde-3-phosphate dehydrogenase and interleukin-2 receptor-α mRNA were not affected. The results support the conclusion that the noncytotoxic anti-HIV response of CD8+ T cells, demonstrable in vitro, does not affect any of the virus replication steps leading to the integration of proviral HIV, but specifically interrupts the expression of viral RNA.

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The chromatin landscape at the HIV-1 provirus integration site determines viral expression

Nucleic Acids Research ◽

10.1093/nar/gkaa536 ◽

2020 ◽

Vol 48 (14) ◽

pp. 7801-7817 ◽

Cited By ~ 3

Author(s):

Gerlinde Vansant ◽

Heng-Chang Chen ◽

Eduard Zorita ◽

Katerina Trejbalová ◽

Dalibor Miklík ◽

...

Keyword(s):

Integration Site ◽

Treatment Interruption ◽

Latent Reservoir ◽

Rna Expression ◽

Direct Link ◽

Viral Expression ◽

Active Transcription ◽

Provirus Integration Site ◽

Provirus Integration ◽

Hiv 1

Abstract HIV-1 persists lifelong in memory cells of the immune system as latent provirus that rebounds upon treatment interruption. Therefore, the latent reservoir is the main target for an HIV cure. Here, we studied the direct link between integration site and transcription using LEDGINs and Barcoded HIV-ensembles (B-HIVE). LEDGINs are antivirals that inhibit the interaction between HIV-1 integrase and the chromatin-tethering factor LEDGF/p75. They were used as a tool to retarget integration, while the effect on HIV expression was measured with B-HIVE. B-HIVE tracks insert-specific HIV expression by tagging a unique barcode in the HIV genome. We confirmed that LEDGINs retarget integration out of gene-dense and actively transcribed regions. The distance to H3K36me3, the marker recognized by LEDGF/p75, clearly increased. LEDGIN treatment reduced viral RNA expression and increased the proportion of silent provirus. Finally, silent proviruses obtained after LEDGIN treatment were located further away from epigenetic marks associated with active transcription. Interestingly, proximity to enhancers stimulated transcription irrespective of LEDGIN treatment, while the distance to H3K36me3 only changed after treatment with LEDGINs. The fact that proximity to these markers are associated with RNA expression support the direct link between provirus integration site and viral expression.

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Provirus integration in [90]Sr -induced osteosarcomas of CFF1 mice

European Journal of Cancer and Clinical Oncology ◽

10.1016/0277-5379(87)90752-8 ◽

1987 ◽

Vol 23 (11) ◽

pp. 1808

Author(s):

E. Van der Rauwelaert ◽

J.R. Maisin ◽

J. Merregaert

Keyword(s):

Provirus Integration

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Human adenosine deaminase expression in mice

Blood ◽

10.1182/blood.v75.10.2085.2085 ◽

1990 ◽

Vol 75 (10) ◽

pp. 2085-2092 ◽

Cited By ~ 29

Author(s):

KA Moore ◽

FA Fletcher ◽

DK Villalon ◽

AE Utter ◽

JW Belmont

Keyword(s):

Stem Cells ◽

Adenosine Deaminase ◽

Bone Marrow Cells ◽

High Titer ◽

Experimental Period ◽

Hematopoietic Stem ◽

Provirus Integration

Abstract A replication defective retroviral vector containing a human adenosine deaminase (hADA) cDNA was produced by GP + E-86 packaging cells at high titer. We report long-term expression of hADA in the hematopoietic tissues of mice transplanted with bone marrow cells infected by in vitro co-cultivation with vector producing cells. Western analysis using an hADA-specific antibody allowed detection of the protein in the peripheral blood of all 37 transplanted mice for at least 9 weeks. Sixty-eight percent of the animals continued to express hADA in one or more of their hematopoietic tissues for the experimental period, and hADA was found in both spleen colonies and tissues of secondary recipients. There was provirus integration and expression in myeloid, erythroid, and lymphoid cell lineages, indicating extensive repopulation by the progeny of infected stem cells. The vector did not contain a selectable marker, and the infected stem cells did not have a competitive in vivo advantage. Nevertheless, we observed consistent gene transfer into hematopoietic stem cells and long-term expression of a human gene product in their progeny.

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