ArticleRetrovirology2006
Effects of prostratin on Cyclin T1/P-TEFb function and the gene expression profile in primary resting CD4+ T cells.
Article in Retrovirology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 78 citations in OpenAlex.
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- Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments.Cancer biology & therapy · 2023Review
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- P-TEFb is degraded by Siah1/2 in quiescent cells.Nucleic acids research · 2022Article
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- Low Inducibility of Latent Human Immunodeficiency Virus Type 1 Proviruses as a Major Barrier to Cure.The Journal of infectious diseases · 2021Review
- Non-coding RNAs in the Pathogenesis of Multiple Sclerosis.Frontiers in genetics · 2021Review
- Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen.PloS one · 2021Article
- A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 Mortality.Pharmaceutical research · 2020Article
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- Latency-Reversing Agents Induce Differential Responses in Distinct Memory CD4 T Cell Subsets in Individuals on Antiretroviral Therapy.Cell reports · 2019Article
- Roles of CDKs in RNA polymerase II transcription of the HIV-1 genome.Transcription · 2019Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe latent reservoir of human immunodeficiency virus type 1 (HIV-1) in resting CD4+ T cells is a major obstacle to the clearance of infection by highly active antiretroviral therapy (HAART). Recent studies have focused on searches for adjuvant therapies to activate this reservoir under conditions of HAART. Prostratin, a non tumor-promoting phorbol ester, is a candidate for such a strategy. Prostratin has been shown to reactivate latent HIV-1 and Tat-mediated transactivation may play an important role in this process. We examined resting CD4+ T cells from healthy donors to determine if prostratin induces Cyclin T1/P-TEFb, a cellular kinase composed of Cyclin T1 and Cyclin-dependent kinase-9 (CDK9) that mediates Tat function. We also examined effects of prostratin on Cyclin T2a, an alternative regulatory subunit for CDK9, and 7SK snRNA and the HEXIM1 protein, two factors that associate with P-TEFb and repress its kinase activity.
resultsProstratin up-regulated Cyclin T1 protein expression, modestly induced CDK9 protein expression, and did not affect Cyclin T2a protein expression. Although the kinase activity of CDK9 in vitro was up-regulated by prostratin, we observed a large increase in the association of 7SK snRNA and the HEXIM1 protein with CDK9. Using HIV-1 reporter viruses with and without a functional Tat protein, we found that prostratin stimulation of HIV-1 gene expression appears to require a functional Tat protein. Microarray analyses were performed and several genes related to HIV biology, including APOBEC3B, DEFA1, and S100 calcium-binding protein genes, were found to be regulated by prostratin.
conclusionProstratin induces Cyclin T1 expression and P-TEFb function and this is likely to be involved in prostratin reactivation of latent HIV-1 proviruses. The large increase in association of 7SK and HEXIM1 with P-TEFb following prostratin treatment may reflect a requirement in CD4+ T cells for a precise balance between active and catalytically inactive P-TEFb. Additionally, genes regulated by prostratin were identified that have the potential to regulate HIV-1 replication both positively and negatively.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.