The Yin and Yang of P-TEFb Regulation: Implications for Human Immunodeficiency Virus Gene Expression and Global Control of Cell Growth and Differentiation

Zhou, Qiang; Yik, Jasper H.N.

doi:10.1128/mmbr.00011-06

Cited by 239 publications

(302 citation statements)

References 123 publications

(206 reference statements)

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“…Brd4 can be an important regulator of Pol-II pausing, releasing P-TEFb from an inactive complex with the transcriptional regulator, HEXIM1, and the 7SK small nuclear ribonuclear protein (snRNP) and bridging its interaction with chromatin by bromodomain-mediated binding to acetylated histones (19,36). We investigated whether, in an analogous fashion, Brd4 links Aire and P-TEFb, and thereby promotes release of paused Pol-II to induce Aire-dependent transcripts.…”

Section: Phosphorylation Of the Aire Card Facilitates Nearby Acetylatmentioning

confidence: 99%

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Yoshida

Bansal

Schaefer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomaincontaining protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.

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Section: Phosphorylation Of the Aire Card Facilitates Nearby Acetylatmentioning

confidence: 99%

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Yoshida

Bansal

Schaefer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…P-TEFb exists in 2 mutually exclusive complexes that differ in their kinase activity (2). A transcriptionally inactive complex [referred to herein as 7SK small nuclear ribonucleoprotein (7SK snRNP)] contains P-TEFb, hexamethylene bisacetamide-induced protein (HEXIM) 1 (HEXIM1) and/or HEXIM2, the noncoding 7SK small nuclear RNA (7SK) and the La-related protein 7 (LARP7) (6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

“…A paradigm for this type of control is the regulation of HIV-1 transcription, which is paused because of concerted actions of the negative transcription elongation factors (N-TEFs) (1,2). The block is reversed by the positive transcription elongation factor b (P-TEFb), consisting of a heterodimer between the cyclin-dependent kinase 9 (Cdk9) and one of the four C-type cyclins (CycT1/T2a(b)/K) (2), which phosphorylates Ser2 within the multiple heptapeptide repeats YSPTSPS of the carboxy-terminal domain (CTD) of the Rpb1 subunit of RNAPII, as well as components of N-TEFs.…”

mentioning

confidence: 99%

7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development

Barborič

Lenasi

Chen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

151

176

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Eukaryotic gene expression is commonly controlled at the level of RNA polymerase II (RNAPII) pausing subsequent to transcription initiation. Transcription elongation is stimulated by the positive transcription elongation factor b (P-TEFb) kinase, which is suppressed within the 7SK small nuclear ribonucleoprotein (7SK snRNP). However, the biogenesis and functional significance of 7SK snRNP remain poorly understood. Here, we report that LARP7, BCDIN3, and the noncoding 7SK small nuclear RNA (7SK) are vital for the formation and stability of a cell stress-resistant core 7SK snRNP. Our functional studies demonstrate that 7SK snRNP is not only critical for controlling transcription elongation, but also for regulating alternative splicing of pre-mRNAs. Using a transient expression splicing assay, we find that 7SK snRNP disintegration promotes inclusion of an alternative exon via the increased occupancy of P-TEFb, Ser2-phosphorylated (Ser2-P) RNAPII, and the splicing factor SF2/ASF at the minigene. Importantly, knockdown of larp7 or bcdin3 orthologues in zebrafish embryos destabilizes 7SK and causes severe developmental defects and aberrant splicing of analyzed transcripts. These findings reveal a key role for P-TEFb in coupling transcription elongation with alternative splicing, and suggest that maintaining core 7SK snRNP is essential for vertebrate development.C hallenging the once predominantly held view that RNA polymerase II (RNAPII) recruitment to promoters is the rate-limiting event in regulating eukaryotic transcription, several recent studies indicate that RNAPII pauses subsequently to transcription initiation at a large number of genes in Drosophila and in several cell lineages in humans (1). A paradigm for this type of control is the regulation of HIV-1 transcription, which is paused because of concerted actions of the negative transcription elongation factors (N-TEFs) (1, 2). The block is reversed by the positive transcription elongation factor b (P-TEFb), consisting of a heterodimer between the cyclin-dependent kinase 9 (Cdk9) and one of the four C-type cyclins (CycT1/T2a(b)/K) (2), which phosphorylates Ser2 within the multiple heptapeptide repeats YSPTSPS of the carboxy-terminal domain (CTD) of the Rpb1 subunit of RNAPII, as well as components of N-TEFs. Of note, P-TEFb is critical for expressing early embryonic genes in C. elegans (3), and experiments in yeast and Drosophila demonstrate that it is also vital for proper 3Ј end pre-mRNA processing (4, 5). Thus, regulating transcription elongation is a key checkpoint for modulating eukaryotic gene expression.P-TEFb exists in 2 mutually exclusive complexes that differ in their kinase activity (2). A transcriptionally inactive complex [referred to herein as 7SK small nuclear ribonucleoprotein (7SK snRNP)] contains P-TEFb, hexamethylene bisacetamide-induced protein (HEXIM) 1 (HEXIM1) and/or HEXIM2, the noncoding 7SK small nuclear RNA (7SK) and the La-related protein 7 (LARP7) (6-12). Therein, 7SK is a molecular scaffold, which binds HEXIM1, HEXIM2, and LARP7 d...

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“…The positive transcription elongation factor b (P-TEFb) 2 is a cellular kinase complex that regulates elongation of most mammalian protein-coding genes transcribed by RNA polymerase II (1,2). P-TEFb enhances the processivity of RNA polymerase II through the phosphorylation of the carboxyl-terminal domain (CTD) of the polymerase as well as antagonizing the actions of negative factors such as negative elongation factor and 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole sensitivity-inducing factor.…”

mentioning

confidence: 99%

Phosphatase PPM1A Regulates Phosphorylation of Thr-186 in the Cdk9 T-loop

Wang¹,

Dow²,

Liang

et al. 2008

Journal of Biological Chemistry

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Cdk9 is the catalytic subunit of a general RNA polymerase II elongation factor known as positive transcription elongation factor b (P-TEFb). The kinase function of P-TEFb requires phosphorylation of Thr-186 in the T-loop of Cdk9 to allow substrates to access the catalytic core of the enzyme. To identify human phosphatases that dephosphorylate the T-loop of Cdk9, we used a Thr-186-phosphospecific antiserum to screen a phosphatase expression library. Overexpression of PPM1A and the related PPM1B greatly reduced Cdk9 T-loop phosphorylation in vivo. PPM1A and Cdk9 appear to associate in vivo as the proteins could be co-immunoprecipitated. The short hairpin RNA depletion of PPM1A resulted in an increase in Cdk9 T-loop phosphorylation. In phosphatase reactions in vitro, purified PPM1A could dephosphorylate Thr-186 both with and without the association of 7SK RNA, a small nuclear RNA that is bound to ϳ50% of total cellular P-TEFb. PPM1B only efficiently dephosphorylated Cdk9 Thr-186 in vitro when 7SK RNA was depleted from P-TEFb. Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function.The positive transcription elongation factor b (P-TEFb) 2 is a cellular kinase complex that regulates elongation of most mammalian protein-coding genes transcribed by RNA polymerase II (1, 2). P-TEFb enhances the processivity of RNA polymerase II through the phosphorylation of the carboxyl-terminal domain (CTD) of the polymerase as well as antagonizing the actions of negative factors such as negative elongation factor and 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole sensitivity-inducing factor. P-TEFb is comprised of cyclin-dependent kinase 9 (Cdk9), the kinase core, and its cyclin partner, either Cyclin T1, Cyclin T2, or Cyclin K. Two isoforms of Cdk9 exist, a major 42-kDa protein and a minor 55-kDa protein that contains 117 residues at the amino terminus that are absent in the 42-kDa protein (3). In most cells examined, Cyclin T1 is the predominant regulatory subunit for Cdk9. The Cyclin T1/P-TEFb complex has been studied extensively as this P-TEFb complex is targeted by the human immunodeficiency virus type 1 Tat protein to activate RNA polymerase II transcription of the integrated provirus, and this is essential for viral replication.As a key transcription factor, the activity of P-TEFb is carefully regulated within the cell. The first level of control is mediated by the regulated expression of its components, namely Cdk9 and its Cyclin partners. In primary human CD4 ϩ T lymphocytes and monocytes, Cdk9 and Cyclin T2 expression are relatively high, whereas that of Cyclin T1 is low. Upon T cell activation or monocyte differentiation, Cyclin T1 protein expression is strongly up-regulated by post-transcriptional mechanisms, whereas expression of Cdk9 and Cyclin T2 remains relatively constant (4 -9). Low levels of Cyclin T1 in resting CD4ϩ T cells and freshly isolated blood monocytes may function as one of the rate-limiting factors not only for transcription of many cellul...

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The Yin and Yang of P-TEFb Regulation: Implications for Human Immunodeficiency Virus Gene Expression and Global Control of Cell Growth and Differentiation

Cited by 239 publications

References 123 publications

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development

Phosphatase PPM1A Regulates Phosphorylation of Thr-186 in the Cdk9 T-loop

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