HIV-1 Tat Interaction with RNA Polymerase II C-terminal Domain (CTD) and a Dynamic Association with CDK2 Induce CTD Phosphorylation and Transcription from HIV-1 Promoter

Deng, Longwen; Ammosova, Tatyana; Pumfery, Anne; Kashanchi, Fatah; Nekhai, Sergeï

doi:10.1074/jbc.m111349200

Cited by 89 publications

(107 citation statements)

References 35 publications

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“…Such broad protein kinase substrate specificity is not too surprising, because Ͼ20 isoforms of CDK11 p110 are produced ubiquitously in all human cells (18). In addition, others have shown that TAT-SF1 U-snRNP complexes containing CDK9 and cyclin T proteins stimulate splicing in vitro, possibly facilitating the reciprocal activation of transcription and splicing events through its ability to function as a dual-function factor (19).…”

mentioning

confidence: 99%

CDK11 Complexes Promote Pre-mRNA Splicing

Mayeda

Trembley

et al. 2003

Journal of Biological Chemistry

142

137

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The PITSLRE protein kinases, hereafter referred to as CDK11 because of their association with the cyclin L regulatory partner, belong to large molecular weight protein complexes that contain RNA polymerase II. These CDK11 p110 complexes have been reported to influence transcription as well as interact with the general pre-mRNA-splicing factor RNPS1. Some of these complexes may also play a role in pre-mRNA splicing. Using a two-hybrid interactive screen, the splicing protein 9G8 was identified as an in vivo partner for CDK11 p110 . The identification of several splicing-related factors as CDK11 p110 interactors along with the close relationship between transcription and splicing indicated that CDK11 p110 might influence splicing activity directly. Immunodepletion of CDK11 p110 from splicing extracts greatly reduced the appearance of spliced products using an in vitro assay system. Moreover, the re-addition of these CDK11 p110 immune complexes to the CDK11 p110 -immunodepleted splicing reactions completely restored splicing activity. Similarly, the addition of purified CDK11 p110 amino-terminal domain protein was sufficient to inhibit the splicing reaction. Finally, 9G8 is a phosphoprotein in vivo and is a substrate for CDK11 p110 phosphorylation in vitro. These data are among the first demonstrations showing that a CDK activity is functionally coupled to the regulation of pre-mRNA-splicing events and further support the hypothesis that CDK11 p110 is in a signaling pathway that may help to coordinate transcription and RNA-processing events.The regulation of transcription and RNA-processing events is complex and, in fact, may be coordinated through the action of several protein kinases that belong to the larger cell division control family (i.e. CDKs) 1 (1-7). These CDKs are not only regulated during the cell cycle, they are undoubtedly part of a much larger signal transduction pathway that is modulated by numerous extracellular and intracellular signals (8). A model is emerging in which the phosphorylation status of the RNA polymerase II (RNAP II) carboxyl-terminal domain (CTD) determines which specific transcription, RNA processing, and polyadenylation factors are recruited to the CTD (5, 7-9). The CTD is heavily phosphorylated in vivo, and a number of protein kinases, particularly CDKs, have been identified that modify this domain in vitro. CDK7, CDK8, and CDK9 are all known CTD protein kinases that regulate different aspects of transcription (10 -13). Sequential phosphorylation of specific amino acid residues within the CTD appears to be regulated by this group of CDKs. These phosphorylation events have been linked to the changes in the composition of RNAP II complexes that are associated with transcription from pre-initiation through termination. However, a functional relationship between a specific CDK and the regulation of pre-mRNA-splicing events has only been inferred (14,15).Based upon the findings reported in this study as well as others (14, 15) demonstrating that the PITSLRE p110 protein kinases associ...

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confidence: 99%

CDK11 Complexes Promote Pre-mRNA Splicing

Mayeda

Trembley

et al. 2003

Journal of Biological Chemistry

142

137

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“…Reports have been published that CDK group, especially the CDK2, is involved in the transcription and replication of Human Immunodeficiency Virus -1 by means of phosphorylation [22], [23]. Previous studies [8], [24] also show that CK2 group phosphorylates Hepatitis C Virus NS5A proteins and Human Immunodeficiency Virus -1 gp120, gp41, p27, and p17 proteins to name a few, on both S and T residues.…”

Section: Motifs Comparisonmentioning

confidence: 99%

Exploiting Two-Layered Support Vector Machine to Predict Phosphorylation Sites on Virus Proteins

Lu¹,

Bretaña²,

Chang³

et al. 2013

IJBBB

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Abstract-Protein phosphorylation in viruses plays crucial regulatory roles in enhancing progression, replication, and inhibition of host cell functions. Due to the difficulty of mass spectrometry-based identification of viral phosphorylation sites, we are motivated to develop a new method to investigate the substrate motifs and identify protein phosphorylation sites on viruses. The experimentally verified phosphorylation data were extracted from a public resource and a recursively statistical method is applied to cluster whole data set of phosphorylated sequences into subgroups containing remarkably sequence motifs around the phosphorylation sites. Two-layered Support Vector Machine (SVM) is then applied to learn a predictive model by integrating the detected sequence motifs. A five-fold cross validation evaluation on the SVM model yields an average accuracy of 0.88 for Serine and 0.83 for Threonine. Furthermore, the independent testing data collected from UniProtKB and Phospho.ELM indicates that the proposed method is comparable with three popular kinase-specific phosphorylation site prediction tools. The cross validation and independent testing demonstrated that the sequence motifs are informative for the prediction of potential kinases for virus protein phosphorylation sites. Furthermore, the proposed method is a practical means of preliminary analysis for virus phosphorylation dynamics.Index Terms-Virus, protein phosphorylation, substrate motif, support vector machine.

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“…Cyclindependent kinase 2 (CDK2) is a catalytic subunit of the cyclindependent protein kinase complex, whose activity is restricted to the G1-S phase, and which is essential for transition of the cell cycle from G1 to S phase. CDK2 phosphorylates HIV Tat protein, a step that is important for HIV-1 transcription [41,42].…”

Section: Ppi Clusters Spanned By Bkz Hdfs and Ss+ Predicted Hdfs Are mentioning

confidence: 99%

Network-Based Prediction and Analysis of HIV Dependency Factors

Murali

Dyer²,

Badger

et al. 2012

Lecture Notes in Computer Science

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HIV Dependency Factors (HDFs) are a class of human proteins that are essential for HIV replication, but are not lethal to the host cell when silenced. Three previous genome-wide RNAi experiments identified HDF sets with little overlap. We combine data from these three studies with a human protein interaction network to predict new HDFs, using an intuitive algorithm called SinkSource and four other algorithms published in the literature. Our algorithm achieves high precision and recall upon cross validation, as do the other methods. A number of HDFs that we predict are known to interact with HIV proteins. They belong to multiple protein complexes and biological processes that are known to be manipulated by HIV. We also demonstrate that many predicted HDF genes show significantly different programs of expression in early response to SIV infection in two non-human primate species that differ in AIDS progression. Our results suggest that many HDFs are yet to be discovered and that they have potential value as prognostic markers to determine pathological outcome and the likelihood of AIDS development. More generally, if multiple genome-wide gene-level studies have been performed at independent labs to study the same biological system or phenomenon, our methodology is applicable to interpret these studies simultaneously in the context of molecular interaction networks and to ask if they reinforce or contradict each other.

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HIV-1 Tat Interaction with RNA Polymerase II C-terminal Domain (CTD) and a Dynamic Association with CDK2 Induce CTD Phosphorylation and Transcription from HIV-1 Promoter

Cited by 89 publications

References 35 publications

CDK11 Complexes Promote Pre-mRNA Splicing

CDK11 Complexes Promote Pre-mRNA Splicing

Exploiting Two-Layered Support Vector Machine to Predict Phosphorylation Sites on Virus Proteins

Network-Based Prediction and Analysis of HIV Dependency Factors

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