ALL LIFE 2020, VOL. 13, NO. 1, 23–33 https://doi.org/10.1080/21553769.2019.1663277 PERSPECTIVES Yan Wang and Tong Qiu Department of Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, People’s Republic of China ABSTRACT ARTICLE HISTORY Received 30 April 2019 Positive transcription factor b (P-TEFb) has emerged as a general and essential factor to release RNA Accepted 29 August 2019 polymerase II from promoter-proximal pausing. Recruitment of P-TEFb by various master develop- mental regulators seems to be a common theme to allow for coordinated gene expression. The KEYWORDS biological outcome is highly dependent on the cellular context as well as the nature of the tran- P-TEFb; physiological scription factor that recruits P-TEFb. Understanding the physiological functions of P-TEFb and its functions; development regulators will certainly have implications in human diseases such as cancer. 1. Introduction II and negative elongation factors, DRB Sensitivity Inducing Factor (DSIF) as well as Negative Elonga- Preciseand coordinatedgeneexpressionliesatthe tion Factor (NELF) (Rahl et al. 2010). And recent heart of many biological processes such as organ- studies have shown that promoter-proximal pausing is ismal development and stress responses to harmful primarily for 5 capping, partially facilitated by inter- environmental stimuli (Little et al. 2013;Paniand action betweenDSIFand cappingenzyme(Wenand Nudler 2017). Like unicellular organisms, multicellu- Shatkin 1999;Mandaletal. 2004). Multicellular organ- lar organisms control the expression of many protein- isms may also have evolved to exploit transcription coding genes at the step of initiation, the process by elongation control to allow for rapid and ecffi ient which RNA polymerase II (RNAP II) assembles at the induction of gene expression to sense environmental promoter with the aid of general as well as various stimuli such as mounting immunological responses to tissue-specific transcription factors. Unwanted gene fight infections (Freaney et al. 2013). expression is shut down without a RNAP II bound to Cellular factors that regulate transcription elon- the promoter (Goodrich and Tjian 2010). In addition gation of RNAP II have been identified (Guo and to initiation, recent studies have demonstrated that Price 2013;Smith andShilatifard 2013;Scheideg- transcriptionelongationisalsoakeyregulatorystep ger and Nechaev 2016). One of the key factors cen- in multicellular organisms including humans, that is, tral to this control is Positive Elongation Factor b RNAP II is paused at the promoter-proximal region (P-TEFb). P-TEFb, composed of cyclin-dependent without generating full-length mRNA (Guo and Price kinase 9 (CDK9) and cyclin T, releases paused 2013; Scheidegger and Nechaev 2016). At a glance, RNAP II into productive elongation via phosphory- it seems to be energetically unfavorable to assemble lation of the carboxyl-terminal domain (CTD) of the RNAP II at the promoter without further transcrip- largest subunit of RNAP II, DSIF as well as NELF tion. Although the logic behind this type of control is (Bartholomeeusen et al. 2012). In cells, the kinase not entirely clear, current evidence strongly suggests activity of P-TEFb is tightly regulated by reversible that preassemblyofRNAPIIatthepromoter maybe association with the 7SK small nuclear ribonucleo- the molecular underpinnings of highly dynamic yet protein complex (snRNP). Dysregulation of P-TEFb precise regulation of gene expression during animal activity has implications in human diseases, exempli- development (Smith and Shilatifard 2013). The sites of fiedbyHIV-1 transcriptioninwhich viralproteinTat promoter-proximal pausing are co-occupied by RNAP CONTACT Tong Qiu email@example.com Department of Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu 610041, People’s Republic of China © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 24 Y. WANG AND T. QIU usurps cellular P-TEFb normally sequestered by 7SK a cellular mechanism to compensate for decreased snRNP to active transcription from the HIV promoter transcriptional activity. Interestingly, inhibitors of (Peterlin and Price 2006). In this review, we summarize histone deacetylases (HDACis) and bromodomain findings in recent literature on roles of P-TEFb and its and extra terminal domain (BETis) can also release regulators in animal development. Understanding the P-TEFb from 7SK snRNP, followed by increased syn- physiological functions of P-TEFb and its regulators thesis of HEXIM1, reassembly of the 7SK snRNP, will shed light on etiology of human diseases such as and ultimately leading to P-TEFb inhibition and cancer because the developmental process and tumori- subsequently reduced cell growth and differentia- genesis are inextricably linked at the molecular level. tion (Bartholomeeusen et al. 2012;Bartholomeeusen For those who are interested in the biochemical aspects et al. 2013). P-TEFb freed from 7SK snRNP may of P-TEFb and its roles in human diseases, please refer be involved in cellular processes other than releasing tootherarticlesinthisissueaswellasrecentexcellent paused RNAP II. These studies have shown that P- review articles on these topics (Guo and Price 2013; TEFb activity is important to mount full DNA damage Smith and Shilatifard 2013;Yuetal. 2015;Francoetal. response (Zhang et al. 2013; Nepomuceno et al. 2017). 2018). It will be of interest in future to identify other cellu- lar targets and pathways regulated by P-TEFb to fully understand the physiological functions of the inactive, 2. Regulation of P-TEFb: small and large forms large form of P-TEFb. of P-TEFb Thecellularmechanismscontrolling assemblyand In mammalian cells, most cellular P-TEFb is disassemblyofthe largeformofP-TEFbarenotwell sequestered by the 7SK snRNP, composed of 7SK small understood. Interestingly, more than 80% of HEXIM1 nuclear RNA (snRNA) (Yang et al. 2001)andat least proteins are not in complex with 7SK snRNA or P- three protein components including hexamethylene TEFb (Li et al. 2005, 2007). The amount of 7SK snRNP bis-acetamide inducible 1 or 2 (HEXIM1 or HEXIM2) in cellsislikelymorethanP-TEFb( ∼ 2 × 10 7SK (Yik et al. 2003), methylphosphate capping enzyme molecules per HeLa cell) (Wassarman and Steitz 1991). (MEPCE) (Jeronimo et al. 2007)andLa ribonucleo- Yet not all P-TEFb are in complex with 7SK snRNP protein domain family, member 7 (LARP7) (He et al. or HEXIM1, indicating that there may be uniden- 2008; Krueger et al. 2008). In this state, termed large tified regulatory factors that control the interaction form, the kinase activity of P-TEFb is inhibited. Bio- between P-TEFb and 7SK snRNP. This also indi- chemical studies demonstrate that 7SK snRNA and cates that HEXIM proteins may have functions other HEXIM proteins together are sufficient to inhibit P- than controlling P-TEFb. Indeed recent studies have TEFb kinase activity in vitro (Li et al. 2005). LARP7 shown that HEXIM1 is required for the innate immune directly binds to 7SK snRNA and appears to maintain response to detect foreign DNA (Morchikh et al. 2017), its steady level in cells while not required to inhibit and regulates leptin function involved in maintaining P-TEFb in vitro (He et al. 2008; Krueger et al. 2008). whole-body energy balance (Dhar-Mascareno et al. MEPCE modifies the 5 end of 7SK snRNA and is also 2016). Furthermore, HEXIM1 can act as a sensor to not required to inhibit P-TEFb in vitro (Jeronimo et al. nucleotide stress and function as a tumour suppres- 2007). A small portion of cellular P-TEFb is free of 7SK sor in melanoma and prostate cancer respectively (Yeh snRNP. In this state, termed small form, P-TEFb can be et al. 2014;Tan et al. 2016). recruited by various factors to the promoter region to Recent genome sequencing studies have identified release paused RNAP II (Peterlin and Price 2006). mutationsinLARP7tobeassociatedwithvarioussolid Stress signals such as ultraviolet (UV) radiation tumors: https://cancer.sanger.ac.uk/cosmic.Specifi- and conditions inducing hypertrophy in cardiomy- cally, several loss-of-function mutations (frameshift ocytes rapidly release P-TEFb from 7SK snRNP (Sano and nonsense mutations) are predicted to gener- et al. 2002). The large form of P-TEFb reforms ate C-terminal truncated LARP7 proteins. As the once stress signals are removed. P-TEFb is also freed C-terminus of LARP7 is required to assemble 7SK from 7SK snRNP when cells are treated with tran- snRNP,theP-TEFbactivity inthesecells arelikelyto scription inhibitors such as flavopiridol and actino- be higher than that in normal cells. Sequencing studies mycin D (Biglione et al. 2007). Presumably it is also identified a large portion of missense mutations in ALL LIFE 25 Table 1. Summary of P-TEFb regulators. Large, inactive P-TEFb complex Gene ID Function RN7SK (Yang et al. 2001) 125050 Sequester and inhibit P-TEFb kinase activity MEPCE (Jeronimo et al. 2007) 56257 LARP7 (He et al. 2008; Krueger et al. 2008) 51574 HEXIM1 or HEXIM2 (Yik et al. 2003) 10614 and 124790 PIE-1 (Ghosh and Seydoux 2008) 176667 PEM (Kumano et al. 2011) 4582 Pgc (Hanyu-Nakamura et al. 2008) 5740599 Sequester P-TEFb kinase Transcription factors and cofactors MED23 (Wang et al. 2013) 9439 Recruit P-TEFb to various promoters to activate transcription; Some of them recruit large, inactive P-TEFb complex HSF1 (Lis et al. 2000) 3297 MYC (NA et al. 2019) 4609 CDK7 (Ebmeier et al. 2017) 1022 MYOD1 (Galatioto et al. 2010;Liu et al. 2017) 4654 GATA1 (Kaneko et al. 2010) 2623 KLF4 (Liu et al. 2014) 9314 IKZF1 (Bottardi et al. 2014) 10320 SOX2 and SOX10 (Arter et al. 2015) 6657 and 6663 YAP1 (Galli et al. 2015) 10,413 ATF4 (Shan et al. 2016) 468 JAK1/STAT3 (Wagner et al. 2015) 3716/6774 AFF1 (Scholz et al. 2015) 4299 Epigenetic regulators TRIM28 (KAP1/TIF1b) (McNamara et al. 2016) 10155 Together with transcription factors and cofactorstorecruit P-TEFb BRD4 (Jang et al. 2005) 23476 SMYD3 (Proserpio et al. 2013) 64754 EP300 (Byun et al. 2009) 2033 Others UBE2O (Faust et al. 2018) 63893 P-TEFb recruitment PPP1CA (Liu et al. 2017) 5499 Initiate and sustain P-TEFb activity by AR BRCA1 (Nepomuceno et al. 2017) 672 co-localize with CDK9 at damaged DNA sites SERPINB2 (Shii et al. 2017) 5055 Mediate P-TEFb recruitment stimulated by LPS cancer cell, scattering all over LARP7 protein. Whether as well as its kinase activity is required for C. elegans these missense mutations have functional outcomes, if development (Shim et al. 2002). In Drosophila,CDK9 any, awaits elucidation (Table 1). depletion disrupts embryo development, and results in avarietyofpatterning defectsinthewing andnotum (Chopra et al. 2009). On the other hand, knockdown 3. P-TEFb is required during early of HEXIM1 is embryonic lethal and exhibits classical embryogenesis wing as well as leg defects. (Nguyen et al. 2012). These results indicate that P-TEFb activity must be tightly P-TEFb is an essential factor during early embryo- regulated for proper metazoan development. genesis in animals. Knockdown of CDK9 in C. ele- Genetic ablation of P-TEFb subunits in mice also gans embryos arrests development at about 100 cells reveals its essential role in early embryogenesis. Cyclin without signs of differentiation. Same phenotype is T2 −/− embryos cease to develop likely before the observed when the largest subunit of RNAP II is 4-cell stage (Kohoutek et al. 2009). Somewhat surpris- knocked down. Like humans, C. elegans genome ingly, cyclin T1–/– mice develop normally except for encodes two cyclin T genes, homologous to human minor immunological defects (Oven et al. 2007). This cyclin T1 and cyclin T2 (Peng et al. 1998). Knockdown could indicate that cyclin T2 may functionally replace of each cyclin T individually does not impair embryo- cyclin T1. Alternatively, leaky expression of cyclin T1 genesis or further development. However, combined observed in knockout mice may be sufficient for devel- knockdown of both cyclin T genes leads to highly sim- opment (Oven et al. 2007). Cyclin K −/− embryos ilar phenotypes as inhibition of CDK9 (Shim et al. dies before the blastocyst stage (Blazek et al. 2011). 2002). Knockdown of P-TEFb also causes diminished Although recombinant cyclin K interacts with CDK9 Ser-2 phosphorylation of RNAP II CTD. Thus P-TEFb 26 Y. WANG AND T. QIU in vitro (Fu et al. 1999), recent studies have shown that HEXIM2 can compensate for HEXIM1 loss in most cyclin K interacts with CDK12 and CDK13 instead organs (Byers et al. 2005). It is not clear why of CDK9 in cells (Blazek et al. 2011). Lethal pheno- HEXIM2 fails to rescue HEXIM1 deficiency specif- typesobservedincyclinT2 −/− embryos predict that ically in hearts. Alternatively, this may also indicate inhibition of P-TEFb will lead to developmental arrest that HEXIM1 has P-TEFb-independent functions in before 4-cell stage. Indeed, pharmaceutical inhibition hearts as most HEXIM1 are not in complex with P- of P-TEFb by flavopiridol results in developmental TEFb (Oakley et al. 2013). Huang et al. have reported arrest at the two-cell stage in mice (Oqani et al. 2016). that defect of HEXIM1 not only lead to cardiac hyper- Collectively, these results demonstrate that P-TEFb is trophybutalsoevenbelethalinlatefetalstages(Huang required for normal development at the earliest stage. et al. 2004). Cardiac hypertrophy-like conditions may In contrast, regulators of P-TEFb such as LARP7 notfully explainthislethalphenotype becauseanimals and HEXIM proteins do not seem to be important can tolerate hypertrophic conditions for an extended for early development. Surprisingly germline loss- time (Maillet et al. 2013). It will be of interest to try of-function mutations in LARP7 lead to primordial to generate HEXIM1 −/− animals in future to fully dwarfism and microcephaly in humans (Najmabadi understand the physiological functions of this protein. Embryonic stem cells (ESCs) are self-renewing, et al. 2011). Consistently, Larp7 −/− mice embryos are pl also smaller than their wild-type counterparts (Oka- uripotent cells derived from the inner cell mass of mura et al. 2012). It is quite paradoxical because loss blastocysts. Under optimal conditions, ESCs can be of LARP7 releases P-TEFb from the large form, and propagated in culture indefinitely (Martello and Smith is expected to increase P-TEFb activity as well as cell 2014). Like germ cells, ESCs need to suppress expres- proliferation, while primordial dwarsfi m is a condi- sion of all somatic programs (Young 2011). Recent tion characterized by global growth failure through- studies have shown that ESCs cultured in serum can out life span (Klingseisen and Jackson 2011). Sev- exist in two interchangeable states (Weinberger et al. eral explanations could potentially account for this 2016). One state, termed naïve state, resembles the paradoxical observation. When LARP7 is knocked inner cell mass. The other more differentiated state, down, there is a significant concomitant decrease in termed the primed state, resembles developmentally P-TEFb protein level (He et al. 2008; Krueger et al. more advanced epiblast. Self-renewal and pluripo- 2008;Daiet al. 2014). This likely will osff et the oth- tency in both states are maintained by the same erwise increased activity. Indeed, transcription from set of core pluripotency transcription factors while HIV-1 LTR, a promoter sensitive to P-TEFb activity, key differences exist. Of note, ESCs in primed state is only slightly upregulated after LARP7 knockdown express detectable lineage-affiliated transcripts (Lee (Krueger et al. 2008). Thus, loss of LARP7 may not et al. 2014). It is a common observation that ESCs significantly increase cell ular P-TEFb activity due to cultured in serum exhibit spontaneous differentiation, a significant concomitant decrease in P-TEFb protein likely because those in the primed state are prone to level. It is also possible that P-TEFb regulation may differentiation. not be the main function of LARP7 as LARP7 inter- Early studies have shown that many lineage- acts with other proteins (Jeronimo et al. 2007; Krueger affiliated geneshavepausedRNAPIIaroundtheir et al. 2008). Finally, ectopic differentiation caused promoters, and propose regulation of transcription by LARP7null-mutationsmayexplaintheetiology elongation is an important mechanism to maintain for primordial dwarfism. However, increased P-TEFb pluripotency (Lin et al. 2011). These studies are car- may not be involved. Instead, loss of LARP7 reduces ried outwithESCsculturedinserum,inwhich LIN28 expression independent of P-TEFb, which in naïve and primed states of ESCs coexist (Ying et al. turn seem to cause untimely differentiation (Dai et al. 2008). Interestingly promoter pausing is more preva- 2014). NoLarp7knockoutadult miceareavailable yet lent in the culture condition termed 2i, which main- simply because the newborn might be eaten (Okamura tains ESCs in naïve state. Precocious transcription et al. 2012). of lineage-affiliated genes in naïve state is restrained Similarly, geneticablationofHEXIM1inmicedoes by RNA polymerase II promoter-proximal pausing. not result in overt cell overproliferation except in In mouse ESCs, 7SK snRNA may function as a hearts (Huang et al. 2004). This could be because multifaceted regulator to repress the expression of ALL LIFE 27 lineage-affiliated genes in a manner both dependent from the chromatin. However, Pgc does not inhibit and independent of P-TEFb (Castelo-Branco et al. the kinase activity of P-TEFb. Loss of Pgc increases 2013). These observations strongly suggest that P- Ser2 phosphorylation in germ cells and leads to germ TEFb activity is tightly controlled in naïve state, and cell degeneration. Ectopic expression of Pgc in somatic in the primed state unknown factors recruit P-TEFb cells is sufficient to suppress Ser2 phosphorylation to promoters of lineage-affiliated genes. Little is known in these cells (Hanyu-Nakamura et al. 2008). Lastly, about the functions of HEXIM1 and LARP7 in ESCs. a study identified posterior end mark (PEM), a key However, knockout studies show that both are not proteininthegermlineofseapineapple Halocynthia essential for early embryogenesis in mice (Huang et al. roretzi, interacts with P-TEFb to suppress Ser2 phos- 2004; Okamura et al. 2012). phorylation globally (Kumano et al. 2011). Low level In summary, P-TEFb is required for animal devel- of Ser2 phosphorylation is also observed in primor- opment at the earliest stage, consistent with its func- dial germ cells in mice (Seki et al. 2007). However, it is tion as an essential, general factor for transcription currently unknown whether there is a specific P-TEFb elongation. In contrast, the physiological functions of inhibitor in mammalian germ cells. Remarkably, PIE- P-TEFb regulators are less clear. Current data sug- 1,Pgcand PEMdonotshareanydetectablesequence similarities, and therefore must have evolved indepen- gest that regulation of P-TEFb may not be essential dently. Yet they converge at interference with P-TEFb for embryonic development, and these regulators may have P-TEFb independent functions. functions in diverse species. 4. Repression of P-TEFb in germ cell 5. Roles of P-TEFb and its regulators in heart, development skeletal muscle, and blood cells In contrast to its essential role in somatic cells dur- In the context of cardiomyocytes, regulation of P-TEFb ing early embryogenesis, P-TEFb activity seems to is tightly linked to cellular growth. Various signals be inhibited in primordial germ cells (PGCs). It is a inducing hypertrophic growth converge at releasing daunting task for germ cells to keep their pluripo- P-TEFb from the large form. Constitutive overex- tent potentials and at the same time not to activate pression of cyclin T in hearts also induces cardiac any somatic genetic programs. Precocious activation hypertrophy (Sano et al. 2002). In another transgenic of any specific cell lineages in germ cells would reduce mouse model in which cardiac hypertrophy condition the number of germ cells and therefore compromise is induced by overexpression of calcineurin, disso- reproduction. Remarkably a global inhibition of Ser2 ciation of HEXIM1 from P-TEFb is observed. Con- phosphorylation of RNAP II CTD seems to be a com- versely genetic ablation of HEXIM1 leads to cardiac mon thread in different species to suppress somatic hypertrophy-like conditions, and further enhances programs and keep their germ cell identify (Robert susceptibility to hypertrophy induced by constitu- tive overexpression of cyclin T in transgenic mice et al. 2015). Interestingly P-TEFb activity is interfered (Espinoza-Derout et al. 2009). And Huang et al. have although underlying molecular mechanisms are dieff r- ent. In C. elegance,PIE-1proteiniscriticalforgermline demonstrated that defect of HEXIM1 also led to be specification (Mello et al. 1996). Part of PIE-1 func- lethal in late fetal stages (Huang et al. 2004). Finally, tion is carried out by binding and inhibiting P-TEFb overexpression of HEXIM1 prevents endothelin-1- through its CTD-mimic motif YAPMAPT (Ghosh and induced cardiac hypertrophy (Yoshikawa et al. 2012). Seydoux 2008). Loss of CDK9 from germ cells has little It is intriguing that in other cellular contexts HEXIM2 effect on Ser2 phosphorylation. It seems that CDK12 can replace HEXIM1 to repress P-TEFb, while in ismainlyresponsiblefor thelowbutdetectableSer2 heartsitfailstodoso(Espinoza-Deroutetal. 2007). phosphorylation in germ cells (Bowman et al. 2013). Another unsolved issue is that in other cell types, Consistently knockdown of CDK9 does not compro- CDK9 protein level is reduced if P-TEFb is released mise germ cell specification by PIE-1 during embryo- from the large complex for an extended period. It does genesis, in contrast to cease of proliferation in somatic not seem to be the case in hearts. Lastly, it is not cells (Shim et al. 2002). In flies, the polar granule com- known how increased P-TEFb activity induces cellular ponent (Pgc) binds P-TEFb and sequesters it away growth in hearts. P-TEFb does not bind DNA or RNA 28 Y. WANG AND T. QIU Figure 1. TheroleofP-TEFbinregulatingRNAPIItranscription. whetherHEXIM2isexpressedin satellitecells,andif by itself. It is a recurring theme that P-TEFb needs to be recruited by transcription factors and chromatin it does, why it fails to rescue the defect of HEXIM1 remodeling proteinsuchasKAP1andMED23(Wang in this cellular context. Cyclin T2 is the major isoform et al. 2013; Di Micco et al. 2014; McNamara et al. 2016) expressed in muscle cells (Marchesi et al. 2013). Inter- (Figure 1). estingly, MyoD, the master regulator of skeletal mus- In a closely related cellular context, the regulation of cles (Pownall et al. 2002), directly interacts with cyclin P-TEFbis showntobeimportantforskeletalmuscle T2, and recruits P-TEFb to activate muscle-specific biology. SMYD3, a histone methyltransferase, medi- genes (Galatioto et al. 2010). In addition to stimulate ates dexamethasone-induced skeletal muscle atro- transcription elongation, P-TEFb directly phosphory- phy in mice via activation of myostatin and c-Met, lates histone H1 and dissociates it from myogenin gene potent inhibitors of muscle cell growth. Mechanisti- promoter regions during differentiation (O’Brien et al. cally SMYD3 recruits BRD4 and subsequently P-TEFb 2012). Thus, the activity of P-TEFb needs to be tightly to release paused RNAP II from the promoters of controlled to maintain skeletal muscle homeostasis. myostain and c-Met. JQ1, a small molecule inhibitor Several master regulators of hematopoiesis seem to of BRD4 (Filippakopoulos et al. 2010), or deletion recruit P-TEFb to regulate their respective genetic pro- of SMYD3 is sufficient to ameliorate dexamethasone- grams. GATA1 is important for the specification and inducedmyotubeatrophy(Proserpioetal. 2013). Con- maintenance of erythroid and megakaryocytic cells versely, activation of P-TEFb from the large form (Kaneko et al. 2010). Mechanistically, GATA1 collab- orateswith otherregulatorssuchasIkarosandLdb1 seems to be required to maintain muscle homeostasis after injury. Upon injuries, quiescent muscle stem cells, to recruit P-TEFb (Song et al. 2010;Bottardietal. termed satellite cells, are activated to proliferate in 2011). Another regulator of erythroid cell develop- order to regenerate muscle mass (Dumont et al. 2015). ment, TIF1gamma, also interacts with P-TEFb to pro- Overexpression of HEXIM1 seems to reduce the rate mote the transcription elongation of erythroid genes of satellite cell expansion, and conversely genetic abla- (Bai et al. 2013). In human T cells, transcription tion of HEXIM1 increases the proliferation of satellite of immediate early genes requires rapid assembly of cells. Theseeeff ctsseemtobemediatedbythereg- p300 and RNAP II at their promoters. p300 further ulation of P-TEFb (Hong et al. 2012). It is not clear recruits BRD4 and P-TEFb to stimulate transcription ALL LIFE 29 Table 2. CDK9 inhibitors in clinical trials. Agent Diseases Development Stage Identiﬁer URL Alvocidib Plus Decitabine Myelodysplastic Syndromes (MDS) Phase 1|Phase 2 NCT03593915 https://ClinicalTrials.gov/show/NCT03593915 AZD4573 Haematological Malignancies Phase 1 NCT03263637 https://ClinicalTrials.gov/show/NCT03263637 BAY1251152 Hematologic Neoplasms Phase 1 NCT02745743 https://ClinicalTrials.gov/show/NCT02745743 P276-00 Melanoma Phase 2 NCT00835419 https://ClinicalTrials.gov/show/NCT00835419 P276-00 Breast Cancer Phase 1 NCT01333137 https://ClinicalTrials.gov/show/NCT01333137 P276-00 Unspeciﬁed Refractory Neoplasms Phase 1 NCT00408018 https://ClinicalTrials.gov/show/NCT00408018 TG02 Astrocytoma, Grade III, Glioblastoma Phase 1 NCT03224104 https://ClinicalTrials.gov/show/NCT03224104 TP-1287 Advanced Solid Tumors Phase 1 NCT03604783 https://ClinicalTrials.gov/show/NCT03604783 elongation. BRD4 and P-TEFb leaves the promoter approaches may provide the solution to this question. once the stimulation signal is removed, while p300 The developmental process and human disease pro- and RNAP II remain bound at the promoter-proximal gression are intertwined at many levels. Understanding the physiological functions of P-TEFb and its regula- region. These bookmarked genes by p300 and RNAP tors will certainly shed light on etiology of disorders II can be readily reactivated by other unrelated stimuli later on (Byun et al. 2009). Defects in master reg- such as cancer and cardiac hypertrophy and facilitate ulators of hematopoiesis frequently lead to human the discovery of novel therapeutic strategies. disorders such as leukemia (Shimizu and Yamamoto 2012). Of note, Table 2 provides P-TEFb inhibitors that Acknowledgment have shown promising effects on leukemia and vari- This work wassupported by West ChinaSecondUniversity ousneoplasminclinicaltrials(Guha 2013;Booe ff tal. Hospital. 2018). Disclosure statement 6. Concluding remarks No potential conflict of interest was reported by the authors. Researchinthelastdecadehasfirmlyestablished P-TEFb as an essential factor in RNAP II elonga- Funding tion regulation. Its activity is mainly regulated by This work was supported by Sprout Research Fund of dynamic association with 7SK snRNP. Recent studies West ChinaSecondUniversityHospital, SichuanUniversity begin to reveal the roles of P-TEFb and its regulators (KX042). under physiological and diseased conditions. A com- mon theme has emerged from these studies, that is, ORCID P-TEFb is recruited by a variety of master develop- Yan Wang http://orcid.org/0000-0002-5076-4282 mental regulators, mainly transcription and epigenetic factors to control genetic programs. This highlights References the importance of P-TEFb in development because transcription factors function together with epigenetic Arter J, Wegner M. 2015. 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Frontiers in Life Science
– Taylor & Francis
Published: Jan 1, 2020
Keywords: P-TEFb; physiological functions; development