Cyclin T1-Dependent Genes in Activated CD4+ T and Macrophage Cell Lines Appear Enriched in HIV-1 Co-Factors

Yu, Wendong; Ramakrishnan, Rajesh; Wang, Yan; Chiang, Karen; Sung, Tzu Ling; Rice, Andrew P.

doi:10.1371/journal.pone.0003146

Cited by 31 publications

(43 citation statements)

References 65 publications

(89 reference statements)

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“…Levels of Cdk9 were reduced slightly, which reflects the almost equivalent levels of CycT1 and CycT2 in these cells. Similar downregulation of Cdk9 in vivo or in cultured cell lines was also reported by other researchers (24,37). Global gene expression profiles were examined with mouse whole-genome microarrays.…”

Section: Figsupporting

confidence: 78%

Cyclin T2 Is Essential for Mouse Embryogenesis

Kohoutek

Blažek

et al. 2009

Molecular and Cellular Biology

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The positive transcription elongation factor b (P-TEFb) is essential for the elongation of transcription and cotranscriptional processing by RNA polymerase II. In mammals, it contains predominantly the C-type cyclin cyclin T1 (CycT1) or CycT2 and cyclin-dependent kinase 9 (Cdk9). To determine if these cyclins have redundant functions or affect distinct sets of genes, we genetically inactivated the CycT2 gene (Ccnt2) using the ␤-galactosidase-neomycin gene (␤-geo) gene trap technology in the mouse. Visualizing ␤-galactosidase during mouse embryogenesis revealed that CycT2 is expressed abundantly during embryogenesis and throughout the organism in the adult. This finding was reflected in the expression of CycT2 in all adult tissues and organs. However, despite numerous matings of heterozygous mice, we observed no CycT2 ؊/؊ embryos, pups, or adult mice. This early lethality could have resulted from decreased expression of critical genes, which were revealed by short interfering RNAs against CycT2 in embryonic stem cells. Thus, CycT1 and CycT2 are not redundant, and these different P-TEFb complexes regulate subsets of distinct genes that are important for embryonic development.Eukaryotic transcription by RNA polymerase II (RNAPII) is regulated at several distinct steps, which include initiation, promoter clearance, elongation, and cotranscriptional processing of primary transcripts (19,25,27). Of these, elongation is regulated by the positive transcription elongation factor b (PTEFb), which contains predominantly the C-type cyclin cyclin T1 (CycT1) or CycT2 and cyclin-dependent kinase 9 (Cdk9). All these different P-TEFb complexes phosphorylate serines at position 2 (S2) in the C-terminal domain (CTD) of RNAPII, as well as components of the negative transcription elongation factor, which contains minimally the DRB (5,6-dichloro-1-␤- D-ribofuranosylbenzimidazole) sensitivity-inducing factor (DSIF) and the negative elongation factor. These posttranslational modifications exchange basal transcription factors for splicing and polyadenylation machineries on RNAPII, as well as modify DSIF for productive elongation (25).Although these P-TEFb complexes can phosphorylate the CTD and lead to transcriptional elongation when recruited to RNAPII via heterologous nucleic acid-tethering systems, it is not clear whether they have redundant or unique functions in cells (18,33). Thus far, CycT1, which is the most abundant of these cyclins, has been implicated as the coactivator of the transcriptional transactivator Tat from human immunodeficiency virus, RelA from NF-B, class II transactivator, the protooncogene c-myc, several members of the steroid hormone receptor family, and the autoimmune regulator AIRE (3, 8, 14-16, 24, 29, 36). Moreover, Runx1, which is the active repressor of CD4 expression in double-negative thymocytes, decoys CycT1 away from the CD4 promoter, thus keeping the

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Section: Figsupporting

confidence: 78%

Cyclin T2 Is Essential for Mouse Embryogenesis

Kohoutek

Blažek

et al. 2009

Molecular and Cellular Biology

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“…The overexpression of miR-27b also negatively affected HIV-1 replication. We previously showed that a large portion of cellular gene expression induced by T cell activation is in fact dependent upon cyclin T1 (53). We show here that the inhibition of individual miRNAs can increase cyclin T1 protein levels in resting CD4 ϩ T cells, indicating that miR-27b, -29b, -150, and -223 significantly contribute to repression of cyclin T1 in vivo.…”

Section: It Is Well Known That Cd4mentioning

confidence: 54%

Regulation of Cyclin T1 and HIV-1 Replication by MicroRNAs in Resting CD4 ⁺ T Lymphocytes

Chiang

Sung

Rice

2012

J Virol

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164

163

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The replication of integrated human immunodeficiency virus type 1 (HIV-1) is dependent on the cellular cofactor cyclin T1, which binds the viral Tat protein and activates the RNA polymerase II transcription of the integrated provirus. The activation of resting CD4؉ T cells upregulates cyclin T1 protein levels independently of an increase in cyclin T1 mRNA levels, suggesting a translational repression of cyclin T1 in resting CD4 ؉ T cells. Hypothesizing that microRNAs (miRNAs) repress cyclin T1 translation in resting CD4؉ T cells and that this inhibition is lifted upon cell activation, we used microarray expression analysis to identify miRNAs miR-27b, miR-29b, miR-150, and miR-223 as being significantly downregulated upon CD4 ؉ T cell activation. The overexpression of these miRNAs decreased endogenous cyclin T1 protein levels, while treatment with the corresponding antagomiRs increased cyclin T1 protein levels. An miR-27b binding site within the cyclin T1 3= untranslated region (3=UTR) was identified and confirmed to be functional after the mutation of key resides abrogated the ability of miR-27b to decrease the expression of a luciferase reporter upstream of the cyclin T1 3=UTR. Ago2 immunoprecipitation revealed an association with cyclin T1 mRNA that was decreased following treatment with miR-27b and miR-29b antagomiRs. Cells overexpressing miR-27b showed decreased viral gene expression levels of the HIV-1 reporter virus and a decreased replication of strain NL4.3; a partial rescue of viral transcription could be seen following the transfection of cyclin T1. These results implicate miR-27b as a novel regulator of cyclin T1 protein levels and HIV-1 replication, while miR-29b, miR-223, and miR-150 may regulate cyclin T1 indirectly.

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“…However, cell lines are immortalized and possess abundant levels of NF-κB and P-TEFb. These important cellular transcription factors are limited in resting CD4+ T cells [21,44]. Therefore, it is important to verify that Euphorbia kansui is not just effective in cell lines.…”

Section: Resultsmentioning

confidence: 99%

Euphorbia Kansui Reactivates Latent HIV

2016

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While highly active anti-retroviral therapy has greatly improved the lives of HIV infected individuals, these treatments are unable to eradicate the virus. Current approaches to reactivate the virus have been limited by toxicity, lack of an orally available therapy, and limited responses in primary CD4+ T cells and in clinical trials. The PKC agonist ingenol, purified from Euphorbia plants, is a potent T cell activator and reactivates latent HIV. Euphorbia kansui itself has been used for centuries in traditional Chinese medicine to treat ascites, fluid retention, and cancer. We demonstrate that an extract of this plant, Euphorbia kansui, is capable of recapitulating T cell activation induced by the purified ingenol. Indeed, Euphorbia kansui induced expression of the early T cell activation marker CD69 and P-TEFb in a dose-dependent manner. Furthermore, Euphorbia kansui reactivated latent HIV in a CD4+ T cell model of latency and in HIV+ HAART suppressed PBMC. When combined with the other latency reversing agents, the effective dose of Euphorbia kansui required to reactive HIV was reduced 10-fold and resulted in synergistic reactivation of latent HIV. We conclude that Euphorbia Euphorbia kansui reactivates latent HIV and activates CD4+ T cells. When used in combination with a latency reversing agent, the effective dose of Euphorbia kansui is reduced; which suggests its application as a combination strategy to reactivate latent HIV while limiting the toxicity due to global T cell activation. As a natural product, which has been used in traditional medicine for thousands of years, Euphorbia kansui is attractive as a potential treatment strategy, particularly in resource poor countries with limited treatment options. Further clinical testing will be required to determine its safety with current anti-retroviral therapies.

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Cyclin T1-Dependent Genes in Activated CD4+ T and Macrophage Cell Lines Appear Enriched in HIV-1 Co-Factors

Cited by 31 publications

References 65 publications

Cyclin T2 Is Essential for Mouse Embryogenesis

Cyclin T2 Is Essential for Mouse Embryogenesis

Regulation of Cyclin T1 and HIV-1 Replication by MicroRNAs in Resting CD4 ⁺ T Lymphocytes

Euphorbia Kansui Reactivates Latent HIV

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Cyclin T1-Dependent Genes in Activated CD4+ T and Macrophage Cell Lines Appear Enriched in HIV-1 Co-Factors

Cited by 31 publications

References 65 publications

Cyclin T2 Is Essential for Mouse Embryogenesis

Cyclin T2 Is Essential for Mouse Embryogenesis

Regulation of Cyclin T1 and HIV-1 Replication by MicroRNAs in Resting CD4 + T Lymphocytes

Euphorbia Kansui Reactivates Latent HIV

Contact Info

Product

Resources

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Regulation of Cyclin T1 and HIV-1 Replication by MicroRNAs in Resting CD4 ⁺ T Lymphocytes