Cross-talk Among RNA Polymerase II Kinases Modulates C-terminal Domain Phosphorylation

Devaiah, Ballachanda N.; Singer, Dinah S.

doi:10.1074/jbc.m112.412015

Cited by 53 publications

(78 citation statements)

References 26 publications

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“…This is consistent with a recent biochemical study reporting an interaction between Brd4 and CDK7 (71). The measured increase in CDK7 binding was not more than 2-to 3-fold, most likely due to antibody affinity and/or instability of TFIIH association with the Nos2 promoter.…”

Section: Discussionsupporting

confidence: 79%

Regulation of NO Synthesis, Local Inflammation, and Innate Immunity to Pathogens by BET Family Proteins

Wienerroither

Rauch

Rosebrock

et al. 2014

Molecular and Cellular Biology

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Section: Discussionsupporting

confidence: 79%

Regulation of NO Synthesis, Local Inflammation, and Innate Immunity to Pathogens by BET Family Proteins

Wienerroither

Rauch

Rosebrock

et al. 2014

Molecular and Cellular Biology

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“…BRD4 and CDK9 are also known to phosphorylate each other (26). In order to determine where and how each factor acts (i.e.…”

Section: Brd4 Is a Decelerator At Moderatementioning

confidence: 99%

“…However, it was recently discovered that BRD4 is a kinase that also phosphorylates the Ser-2 of the RNA Pol II CTD, facilitating the transition of RNA Pol II from initiation to elongation (24,25). Thus, BRD4 is an active participant in transcription (9,24,26). Furthermore, BRD4 participates in coordinating the early steps of transcription initiation and elongation through its interactions with and cross-regulations of P-TEFb and the general transcription factor TFIIH (24,26).…”

mentioning

confidence: 99%

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Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction

Pradhan¹,

Blackford²,

Devaiah³

et al. 2016

Journal of Biological Chemistry

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Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF)-E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (A max ) and the steroid concentration required for half-maximal induction (EC 50 ) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps. The action at two of these steps is dependent on BRD4 concentration, whereas the third step requires the association of BRD4 with P-TEFb. BRD4 is also found to bind to NELF-E, a component of the NELF complex. Unexpectedly, NELF-E modifies GR induction in a manner that is independent of the NELF complex. Several of the kinetically defined steps of BRD4 in this study are proposed to be related to its known biochemical actions. However, novel actions of BRD4 and of NELF-E in GR-controlled gene induction have been uncovered. The model-based competition assay is also unique in being able to order, for the first time, the sites of action of the various reaction components: GR < Cdk9 < BRD4 < induced gene < NELF-E. This ability to order factor actions will assist efforts to reduce the side effects of steroid treatments.Steroid hormone action has been studied intensively since the discovery of steroid hormone receptors almost 50 years ago (1) for three reasons. First, the receptors are obligatory mediators for the biological responses of the five classes of endogenous steroid hormones. Second, steroids and their receptors provide an ideal system in which to define the molecular mechanisms that regulate the controlled induction of gene transcription. Such studies have resulted in the identification of many species or factors that are required for transcription initiation, elongation, and termination (2-4). Third, the clinical benefits of steroid hormones are often severely limited by undesired side effects (5-8). A better molecular understanding of steroid action should lead to fewer side effects, which would significantly expand the clinical applications of steroids in treating human pathologies.The majority of factors identified to date for steroid-regulated gene induction participate in the early steps of transcription initiation (e.g. chromatin remodeling, assembly of the transcription preinitiation complex, and synthesis of the first oligonucleotides) (9). Two interesting classes of factors for steroid-regulated gene transcription are coactivators and corepressors (2-4). One of the earliest and most widely studied of these factors is TIF2/GRIP1, which is a member of the p160 family of coactivators with molecular masses of about 160 kDa (10, 11). Despite the detailed understanding of many of the factors involv...

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“…During PolII transcription, TFIIH associates with other TFIIs and with PolII, and it phosphorylates the CTD of PolII and TFIIE (reviewed in [31][32][33]). For its DNA repair function during NER TFIIH is recruited to the damage site by associating with repairspecific factors (CSA, CSB, or XPC/hHR23, reviewed by [34]).…”

Section: Transcription and Dna Repairmentioning

confidence: 99%

Cross Talk between Cellular Regulatory Networks Mediated by Shared Proteins

Dolde

Suter

2014

Advances in Biology

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Moonlighting proteins mediate cross talk between different pathways and cellular control networks. Sometimes, they even coordinate subsequent steps in the same pathway. For this Outlook paper we asked the question, which cellular processes employ multifunctional proteins (MFPs) and what makes them so attractive to cells and organisms. After reviewing their widespread occurrence, we will focus on higher eukaryotic model systems and on few examples that are linked to ongoing work in our laboratory. We will discuss the activities of transcription factor IIH (TFIIH), and its subcomplexes containing Xpd and Cdk7, and we will cover an aminoacyl-tRNA synthetase (LysRS) and DEAD box RNA helicases. Furthermore, we will analyze how cells are able to properly regulate the different biological activities of multifunctional proteins and which advantages such proteins offer to cells and organisms. Finally we also note that the proteins we discuss are linked to tumor formation or recruited by viruses that coopt the multifunctional protein for yet another purpose.

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Cross-talk Among RNA Polymerase II Kinases Modulates C-terminal Domain Phosphorylation

Cited by 53 publications

References 26 publications

Regulation of NO Synthesis, Local Inflammation, and Innate Immunity to Pathogens by BET Family Proteins

Regulation of NO Synthesis, Local Inflammation, and Innate Immunity to Pathogens by BET Family Proteins

Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction

Cross Talk between Cellular Regulatory Networks Mediated by Shared Proteins

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