Genomes and Genes
positive transcriptional elongation factor b
Summary: A transcriptional elongation factor complex that is comprised of a heterodimer of CYCLIN-DEPENDENT KINASE 9 and one of several CYCLINS including TYPE T CYCLINS and cyclin K. It functions by phosphorylating the carboxy-terminal domain of RNA POLYMERASE II.
- Herrmann C, Rice A. Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. J Virol. 1995;69:1612-20 pubmed..Taken together, these results imply that TAK is a very promising candidate for a cellular factor that mediates Tat transactivation. ..
- ..These results strongly implicate RNA polymerase II elongation control as a major regulator of differentiation and development. ..
- Yokoyama A, Lin M, Naresh A, Kitabayashi I, Cleary M. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell. 2010;17:198-212 pubmed publisher..Thus, AEP recruitment is an integral part of both physiological and pathological MLL-dependent transcriptional pathways. Bypass of its normal recruitment mechanisms is the strategy most frequently used by MLL oncoproteins. ..
- Young T, Tsai M, Tian B, Mathews M, PE ERY T. Cellular mRNA activates transcription elongation by displacing 7SK RNA. PLoS ONE. 2007;2:e1010 pubmed..This represents the first example of a cellular mRNA that can regulate transcription via P-TEFb. Our findings offer a rationale for 7SK being an RNA transcriptional regulator and suggest a practical means for enhancing gene expression. ..
- Cheng B, Price D. Properties of RNA polymerase II elongation complexes before and after the P-TEFb-mediated transition into productive elongation. J Biol Chem. 2007;282:21901-12 pubmed..Our results have uncovered important properties of elongation complexes that allow a more complete understanding of how P-TEFb controls the elongation phases of transcription by RNA polymerase II. ..
- Contreras X, Schweneker M, Chen C, McCune J, Deeks S, Martin J, et al. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem. 2009;284:6782-9 pubmed publisher..Thus SAHA, which is a Food and Drug Administration-approved drug, might be considered to accelerate the decay of the latent reservoir in HAART-treated infected humans...
- He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010;38:428-38 pubmed publisher..The ability of Tat to enable two different classes of elongation factors to cooperate and coordinate their actions on the same polymerase enzyme explains why Tat is such a powerful activator of HIV-1 transcription. ..
- Viladevall L, St Amour C, Rosebrock A, Schneider S, Zhang C, Allen J, et al. TFIIH and P-TEFb coordinate transcription with capping enzyme recruitment at specific genes in fission yeast. Mol Cell. 2009;33:738-51 pubmed publisher..In vitro, phosphorylation of the CTD by Mcs6 stimulates subsequent phosphorylation by Cdk9. We propose that TFIIH primes the CTD and promotes recruitment of P-TEFb/Pcm1, serving to couple elongation and capping of select pre-mRNAs. ..
- Ogba N, Doughman Y, Chaplin L, Hu Y, Gargesha M, Watanabe M, et al. HEXIM1 modulates vascular endothelial growth factor expression and function in breast epithelial cells and mammary gland. Oncogene. 2010;29:3639-49 pubmed publisher..Taken together, our data provide evidence to suggest a novel role for HEXIM1 in cancer progression. ..
- Dulac C, Michels A, Fraldi A, Bonnet F, Nguyen V, Napolitano G, et al. Transcription-dependent association of multiple positive transcription elongation factor units to a HEXIM multimer. J Biol Chem. 2005;280:30619-29 pubmed..Multiple P-TEFb modules are found in the inactive P-TEFb.HEXIM1.7SK complexes. It is proposed that 7SK RNA binding to a HEXIM1 multimer promotes the simultaneous recruitment and hence inactivation of multiple P-TEFb units. ..
- Yang X, Gold M, Tang D, Lewis D, Aguilar Cordova E, Rice A, et al. TAK, an HIV Tat-associated kinase, is a member of the cyclin-dependent family of protein kinases and is induced by activation of peripheral blood lymphocytes and differentiation of promonocytic cell lines. Proc Natl Acad Sci U S A. 1997;94:12331-6 pubmed
- Fujinaga K, Irwin D, Geyer M, Peterlin B. Optimized chimeras between kinase-inactive mutant Cdk9 and truncated cyclin T1 proteins efficiently inhibit Tat transactivation and human immunodeficiency virus gene expression. J Virol. 2002;76:10873-81 pubmed..This chimera inhibited Tat transactivation and HIV gene expression in human cells. Therefore, this dominant-negative kinase-inactive mutant Cdk9.hCycT1 chimera could be used for antiviral gene therapy. ..
- Nguyen V, Kiss T, Michels A, Bensaude O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature. 2001;414:322-5 pubmed..The transcription-dependent interaction of P-TEFb with 7SK may therefore contribute to an important feedback loop modulating the activity of RNA Pol II. ..
- Wang Q, Young T, Mathews M, PE ERY T. Developmental regulators containing the I-mfa domain interact with T cyclins and Tat and modulate transcription. J Mol Biol. 2007;367:630-46 pubmed..Our findings link I-mfa and HIC to viral replication, and suggest that P-TEFb is modulated in the Wnt signaling pathway. ..
- Peng J, Zhu Y, Milton J, Price D. Identification of multiple cyclin subunits of human P-TEFb. Genes Dev. 1998;12:755-62 pubmed..Cotransfection experiments indicated that all three CDK9/cyclin combinations dramatically activated the CMV promoter. ..
- Boehm D, Calvanese V, Dar R, Xing S, Schroeder S, Martins L, et al. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle. 2013;12:452-62 pubmed publisher..Collectively, our results identify BRD2 as a new Tat-independent suppressor of HIV transcription in latently infected cells and underscore the therapeutic potential of BET inhibitors in the reversal of HIV latency. ..
- Karn J. Tackling Tat. J Mol Biol. 1999;293:235-54 pubmed..Tat is able to form a ternary complex with TAR RNA and cyclin T1 only when a functional loop sequence is present on TAR. ..
- Tahirov T, Babayeva N, Varzavand K, Cooper J, Sedore S, Price D. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature. 2010;465:747-51 pubmed publisher..Importantly, Tat induces significant conformational changes in P-TEFb. This finding lays a foundation for the design of compounds that would specifically inhibit the Tat.P-TEFb complex and block HIV replication. ..
- Ghose R, Liou L, Herrmann C, Rice A. Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. J Virol. 2001;75:11336-43 pubmed..These results suggest that induction of TAK by cytokines secreted in the microenvironment of lymphoid tissue may be involved in the reactivation of HIV-1 in CD4(+) T lymphocytes harboring a latent provirus. ..
- Prasanth K, Camiolo M, Chan G, Tripathi V, Denis L, Nakamura T, et al. Nuclear organization and dynamics of 7SK RNA in regulating gene expression. Mol Biol Cell. 2010;21:4184-96 pubmed publisher..Our results suggest that 7SK RNA plays a role in modulating the available level of P-TEFb upon transcriptional down-regulation by sequestering its constituents in nuclear speckles. ..
- Shim E, Walker A, Shi Y, Blackwell T. CDK-9/cyclin T (P-TEFb) is required in two postinitiation pathways for transcription in the C. elegans embryo. Genes Dev. 2002;16:2135-46 pubmed
- Chiu Y, Cao H, Jacque J, Stevenson M, Rana T. Inhibition of human immunodeficiency virus type 1 replication by RNA interference directed against human transcription elongation factor P-TEFb (CDK9/CyclinT1). J Virol. 2004;78:2517-29 pubmed
- Haaland R, Herrmann C, Rice A. Increased association of 7SK snRNA with Tat cofactor P-TEFb following activation of peripheral blood lymphocytes. AIDS. 2003;17:2429-36 pubmed
- Yamada T, Yamaguchi Y, Inukai N, Okamoto S, Mura T, Handa H. P-TEFb-mediated phosphorylation of hSpt5 C-terminal repeats is critical for processive transcription elongation. Mol Cell. 2006;21:227-37 pubmed..We propose the "mini-CTD" hypothesis, in which phosphorylated CTR is thought to function in a manner analogous to phosphorylated CTD, serving as an additional code for active elongation complexes. ..
- Barboric M, Nissen R, Kanazawa S, Jabrane Ferrat N, Peterlin B. NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell. 2001;8:327-37 pubmed..Remarkably, DRB inhibition sensitized cells to TNF-alpha-induced apoptosis. Thus, NF-kappaB requires P-TEFb to stimulate the elongation of transcription and P-TEFb plays an unexpected role in regulating apoptosis. ..
- Lee D, Duan H, Chang C. Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation. J Biol Chem. 2001;276:9978-84 pubmed..Taken together, our reports suggest that AR interacts with TFIIH and P-TEFb and enhances the elongation stage of transcription. ..
- Garber M, Mayall T, Suess E, Meisenhelder J, Thompson N, Jones K. CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA. Mol Cell Biol. 2000;20:6958-69 pubmed..Taken together, these results demonstrate that CDK9 phosphorylation is required for high-affinity binding of Tat-P-TEFb to TAR RNA and that the state of P-TEFb phosphorylation may regulate Tat transactivation in vivo. ..
- Rera M, Bahadorani S, Cho J, Koehler C, Ulgherait M, Hur J, et al. Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab. 2011;14:623-34 pubmed publisher..Our findings point to the possibility that alterations in PGC-1 activity in high-turnover tissues, such as the intestine, may be an important determinant of longevity in mammals. ..
- Barboric M, Taube R, Nekrep N, Fujinaga K, Peterlin B. Binding of Tat to TAR and recruitment of positive transcription elongation factor b occur independently in bovine immunodeficiency virus. J Virol. 2000;74:6039-44 pubmed
- Cho W, Jang M, Huang K, Pise Masison C, Brady J. Human T-lymphotropic virus type 1 Tax protein complexes with P-TEFb and competes for Brd4 and 7SK snRNP/HEXIM1 binding. J Virol. 2010;84:12801-9 pubmed publisher..Our studies have identified Tax as a regulator of P-TEFb that is capable of affecting the balance between its association with the large inactive complex and the small active complex. ..
- Wang Y, Dow E, Liang Y, Ramakrishnan R, Liu H, Sung T, et al. Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop. J Biol Chem. 2008;283:33578-84 pubmed publisher..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. ..
- Rice A, Herrmann C. Regulation of TAK/P-TEFb in CD4+ T lymphocytes and macrophages. Curr HIV Res. 2003;1:395-404 pubmed..These findings suggest that changes in cyclin T1 expression can influence HIV-1 replication levels in monocytes and macrophages. Important areas for future research on Tat and TAK/P-TEFb function are discussed. ..
- Michels A, Nguyen V, Fraldi A, Labas V, Edwards M, Bonnet F, et al. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol Cell Biol. 2003;23:4859-69 pubmed
- Eilebrecht S, Wilhelm E, Benecke B, Bell B, Benecke A. HMGA1 directly interacts with TAR to modulate basal and Tat-dependent HIV transcription. RNA Biol. 2013;10:436-44 pubmed publisher..Our results support a model in which the HMGA1/TAR interaction prevents the binding of transcription-activating cellular co-factors and Tat, subsequently leading to reduced HIV-1 transcription...
- Kruse U, Pallasch C, Bantscheff M, Eberhard D, Frenzel L, Ghidelli S, et al. Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells. Leukemia. 2011;25:89-100 pubmed publisher..Staurosporine and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action. The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development. ..
- Cho S, Schroeder S, Kaehlcke K, Kwon H, Pedal A, Herker E, et al. Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. EMBO J. 2009;28:1407-17 pubmed publisher..These findings support the model that acetylation of cyclin T1 serves as a physiological switch that liberates P-TEFb from its endogenous inhibitors Hexim1 and 7SK snRNA, but is not required for the cooperative action with HIV Tat. ..
- Belanger F, Baigude H, Rana T. U30 of 7SK RNA forms a specific photo-cross-link with Hexim1 in the context of both a minimal RNA-binding site and a fully reconstituted 7SK/Hexim1/P-TEFb ribonucleoprotein complex. J Mol Biol. 2009;386:1094-107 pubmed..Our results demonstrate directly that the Hexim1 binding site is located in the 24-87 region of 7SK RNA and that the protein residues outside the basic domain of Hexim1 are involved in specific RNA interactions. ..
- Turano M, Napolitano G, Dulac C, Majello B, Bensaude O, Lania L. Increased HEXIM1 expression during erythroleukemia and neuroblastoma cell differentiation. J Cell Physiol. 2006;206:603-10 pubmed..Moreover, ectopic expression of HEXIM1 causes growth inhibition and promotes neuronal differentiation. These findings highlight a crucial role of HEXIM1 protein during cell differentiation. ..
- Young T, Wang Q, PE ERY T, Mathews M. The human I-mfa domain-containing protein, HIC, interacts with cyclin T1 and modulates P-TEFb-dependent transcription. Mol Cell Biol. 2003;23:6373-84 pubmed..The isolated I-mfa domain acts as a dominant negative inhibitor. Activation of the HIV-1 LTR by HIC in NIH 3T3 cells occurs at the RNA level and is mediated by direct interactions with P-TEFb. ..
- Chao S, Price D. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem. 2001;276:31793-9 pubmed..Finally, we compared the ability of flavopiridol and DRB to inhibit transcription in vivo using nuclear run-on assays and concluded that P-TEFb is required for transcription of most RNA polymerase II molecules in vivo. ..
- Wada T, Takagi T, Yamaguchi Y, Watanabe D, Handa H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J. 1998;17:7395-403 pubmed..Taken together, this study reveals a molecular basis for DRB action and suggests that P-TEFb stimulates elongation by alleviating the negative action of DSIF. ..
- Fujinaga K, Cujec T, Peng J, Garriga J, Price D, Grana X, et al. The ability of positive transcription elongation factor B to transactivate human immunodeficiency virus transcription depends on a functional kinase domain, cyclin T1, and Tat. J Virol. 1998;72:7154-9 pubmed..Moreover, P-TEFb binds to TAR only in the presence of Tat. We conclude that Tat-P-TEFb complexes bind to TAR, where CDK9 modifies RNA polymerase II for the efficient copying of the viral genome. ..
- Haaland R, Herrmann C, Rice A. siRNA depletion of 7SK snRNA induces apoptosis but does not affect expression of the HIV-1 LTR or P-TEFb-dependent cellular genes. J Cell Physiol. 2005;205:463-70 pubmed..Importantly, depletion of 7SK was found to cause apoptosis by 72 h post-transfection in HeLa cells. These results suggest that 7SK may provide an essential cellular function whose relation to P-TEFb function is unclear. ..
- Zhou M, Halanski M, Radonovich M, Kashanchi F, Peng J, Price D, et al. Tat modifies the activity of CDK9 to phosphorylate serine 5 of the RNA polymerase II carboxyl-terminal domain during human immunodeficiency virus type 1 transcription. Mol Cell Biol. 2000;20:5077-86 pubmed..These studies suggest that the ability of Tat to increase transcriptional elongation may be due to its ability to modify the substrate specificity of the CDK9 complex. ..
- Garber M, Wei P, Jones K. HIV-1 Tat interacts with cyclin T1 to direct the P-TEFb CTD kinase complex to TAR RNA. Cold Spring Harb Symp Quant Biol. 1998;63:371-80 pubmed
- Zhu Y, PE ERY T, Peng J, Ramanathan Y, Marshall N, Marshall T, et al. Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes Dev. 1997;11:2622-32 pubmed