PITALRE, the Catalytic Subunit of TAK, Is Required for Human Immunodeficiency Virus Tat Transactivation In Vivo

Gold, Moses O.; Yang, Xinzhen; Herrmann, Christine; Rice, Andrew P.

doi:10.1128/jvi.72.5.4448-4453.1998

Cited by 113 publications

(36 citation statements)

References 49 publications

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“…In addition to P-TEFb (Yu et al, 2008), CaM has been reported to regulate the expression of PCNA (Maga et al, 1997) and this may be the reason that W-7 treatment inhibited PCNA expression more than HIV-1 LTR expression. Although, P-TEFb has been reported to be recruited by HTLV-1 Tax to activate HTLV-1-LTR (Zhou et al, 2006;Cho et al, 2010), we have reported that a dominantnegative Cdk9 protein does not inhibit Tax transactivation (Gold et al, 1998). Our finding that W-7 reduces Cdk9 T-loop phosphorylation levels, but not Tax activation function are consistent with our previous result with the dominant-negative Cdk9 protein and suggest that the mechanism of Tax transactivation is not as stringently dependent upon P-TEFb as that of the HIV-1 Tat protein.…”

Section: Cdk9 Protein Function Is Modulated By Cdk9 T-loop Phosphorylmentioning

confidence: 56%

“…Furthermore, to verify if the effect of inhibiting Ca 2þ signaling is specific for promoters that have a strong requirement for P-TEFb function, we used a HTLV-1-LTR luciferase expression plasmid in conjunction with its transactivator Tax. We have previously shown that a dominant-negative Cdk9 protein does not inhibit Tax transactivation of the HTLV-1 LTR unlike its strong inhibition of Tat transactivation of the HIV-1 LTR, suggesting that Tax function may not be strictly dependent upon P-TEFb (Gold et al, 1998).…”

Section: Inhibitors Of Ca 2r Signaling Pathway Components Reduce Cdk9mentioning

confidence: 99%

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Cdk9 T‐loop phosphorylation is regulated by the calcium signaling pathway

Ramakrishnan

Rice

2011

Journal Cellular Physiology

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Eukaryotic RNA polymerase II transcriptional elongation is a tightly regulated process and is dependent upon positive transcription elongation factor-b (P-TEFb). The core P-TEFb complex is composed of Cdk9 and Cyclin T and is essential for the expression of most protein coding genes. Cdk9 kinase function is dependent upon phosphorylation of Thr186 in its T-loop. In this study, we examined kinases and signaling pathways that influence Cdk9 T-loop phosphorylation. Using an RNAi screen in HeLa cells, we found that Cdk9 T-loop phosphorylation is regulated by Calcium/Calmodulin- dependent kinase 1D (CaMK1D). Using small molecules inhibitors in HeLa cells and primary CD4+ T lymphocytes, we found that the Ca2+ signaling pathway is required for Cdk9 T-loop phosphorylation. Inhibition of Ca2+ signaling led to dephosphorylation of Thr186 on Cdk9. In reporter plasmid assays, inhibition of the Ca2+ signaling pathway repressed the PCNA promoter and HIV-1 Tat transactivation of the HIV-1 LTR, but not HTLV-1 Tax transactivation of the HTLV-1 LTR, suggesting that perturbation of the Ca2+ pathway and reduction of Cdk9 T-loop phosphorylation inhibits transcription units that have a rigorous requirement for P-TEFb function.

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Section: Cdk9 Protein Function Is Modulated By Cdk9 T-loop Phosphorylmentioning

confidence: 56%

Section: Inhibitors Of Ca 2r Signaling Pathway Components Reduce Cdk9mentioning

confidence: 99%

Cdk9 T‐loop phosphorylation is regulated by the calcium signaling pathway

Ramakrishnan

Rice

2011

Journal Cellular Physiology

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“…Tat copuri es with a nuclear Tat-associated kinase (TAK) (27 ), which corresponds to the kinase subunit of the P-TEFb complex (28,29). The catalytic subunit of this Cdc2-related kinase is PITALRE/ CDK9 (30).…”

Section: Tat and Transcriptional Elongationmentioning

confidence: 99%

Multiple Modes of Transcriptional Regulation by the HIV‐1 Tat Transactivator

Marcello

Zoppé²,

Giacca³

2001

IUBMB Life

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SummaryRegulation of HIV-1 gene expression by the viral Tat transactivator is a critical step in the viral life cycle. Tat acts as a highly unusual transcription factor that interacts with a stem-loop RNA structure (TAR) found at the 5 0 end of all viral transcripts. There, it induces a modi cation of chromatin at the HIV-1 long terminal repeat (LTR) promoter and stimulates the recruitment of elongationcompetent RNA polymerase II complexes capable of processive transcription. Increase of transcriptional elongation is the consequence of the interaction of Tat with cyclin T1, the cyclin component of CDK9, which phosphorylates the carboxy-terminal domain of RNA polymerase II to enhance its processivity. Tat-induced transcriptional activation of the LTR promoter is concomitant with recruitment of the transcriptional coactivators p300 and the highly homologue cAMP-responsive transcription factor binding protein (CBP). These large proteins act at the level of transcriptional initiation by bridging the basal transcription machinery with speci c transcriptional activators. Furthermore, p300/CBP are histone acetyl-transferases capable of modulating the interaction of nucleosomes with DNA and with chromatin remodeling complexes. Besides histones, Tat itself is a substrate for the enzymatic activity of p300/CBP and of the associated factor P/CAF, suggesting a regulatory role of acetylation on the protein itself. Devising a unifying model for LTR activation that includes activities of Tat at the levels of both transcriptional initiation and transcriptional elongation is a challenging task at this moment. Nevertheless, protein localization studies indicate that both cyclin T1 and p300/CBP co-localize in speci c subnuclear compartments, thus suggesting participation of both proteins in the formation of multimolecular complexes governing coordinated steps of transcriptional activation.

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“…As we do not have access to a bTat-specific antiserum, we performed this mutational analysis in the context of an HIV-1 Rev-bTat fusion protein that can be readily detected using an anti-Rev antiserum. Further, in the case of hTat, we and others have previously demonstrated that an hTat-Rev fusion protein can potently activate an HIV-1 LTR in which the hTAR element has been replaced with Rev response element stem-loop IIB (SLIIB), the RNA target for HIV-1 Rev (19,26,34). As shown in Fig.…”

Section: Resultsmentioning

confidence: 91%

“…This binding, which is highly cooperative, is mediated by direct interactions between the Tat basic domain and a TAR RNA bulge and, most probably, between CycT1 and the terminal TAR loop (12,26,32,38,41). Subsequently, the cdk9 component of P-TEFb is believed to activate efficient elongation from the HIV-1 LTR promoter by phosphorylating the carboxyterminal domain of initiated RNA polymerase II molecules, and also possibly other substrates (3, 10, 19,27,35,38,[40][41][42]. Recent evidence demonstrating that the HIV-1 LTR can be fully activated if P-TEFb is recruited to the promoter by tethering to a heterologous RNA target (3,19) suggests that P-TEFb recruitment, either by Tat or by some other means, is both necessary and sufficient for activation of viral transcription.…”

Section: Discussionmentioning

confidence: 99%

Functional Differences between Human and Bovine Immunodeficiency Virus Tat Transcription Factors

et al. 2000

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Transcriptional transactivation of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) promoter element by the essential viral Tat protein requires recruitment of positive transcription elongation factor b (P-TEFb) to the viral TAR RNA target. The recruitment of P-TEFb, which has been proposed to be necessary and sufficient for activation of viral gene expression, is mediated by the highly cooperative interaction of Tat and cyclin T1, an essential component of P-TEFb, with the HIV-1 TAR element. Species, such as rodents, that encode cyclin T1 variants that are unable to support TAR binding by the Tat-cyclin T1 heterodimer are also unable to support HIV-1 Tat function. In contrast, we here demonstrate that the bovine immunodeficiency virus (BIV) Tat protein is fully able to bind to BIV TAR both in vivo and in vitro in the absence of any cellular cofactor. Nevertheless, BIV Tat can specifically recruit cyclin T1 to the BIV TAR element, and this recruitment is as essential for BIV Tat function as it is for HIV-1 Tat activity. However, because the cyclin T1 protein does not contribute to TAR binding, BIV Tat is able to function effectively in cells from several species that do not support HIV-1 Tat function. Thus, BIV Tat, while apparently dependent on the same cellular cofactor as the Tat proteins encoded by other lentiviruses, is nevertheless unique in terms of the mechanism used to recruit the BIV Tat-cyclin T1 complex to the viral LTR promoter.

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PITALRE, the Catalytic Subunit of TAK, Is Required for Human Immunodeficiency Virus Tat Transactivation In Vivo

Cited by 113 publications

References 49 publications

Cdk9 T‐loop phosphorylation is regulated by the calcium signaling pathway

Cdk9 T‐loop phosphorylation is regulated by the calcium signaling pathway

Multiple Modes of Transcriptional Regulation by the HIV‐1 Tat Transactivator

Functional Differences between Human and Bovine Immunodeficiency Virus Tat Transcription Factors

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