Purification of P-TEFb, a Transcription Factor Required for the Transition into Productive Elongation

Marshall, Nicholas F.; Price, David H.

doi:10.1074/jbc.270.21.12335

Cited by 480 publications

(445 citation statements)

References 30 publications

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“…Serum-dependent CTD phosphorylation correlates well with the activation of MAPKs, and depletion of ERK-1/2 from cell extracts results in a loss of serum-stimulated CTD kinase activity (Dubois et al, 1994). In addition, serum-stimulated CTD kinase activity is resistant to inhibiton by the drug 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) (Dubois et al, 1994;Bonnet et al, 1999), which inhibits CDK7, CDK8, and CDK9 but not ERK-1/2 CTD kinase (Marshall and Price, 1995;Yankulov et al, 1995;Rickert et al, 1999). Finally, recombinant ERK-1/2 has been shown to ef®ciently phosphorylate the RNAP II CTD in vitro (Trigon et al, 1998;Bonnet et al, 1999).…”

Section: Cdks Associated With the Rnap II Transcription Machinerymentioning

confidence: 99%

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

Oelgeschläger

2002

Journal Cellular Physiology

128

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The carboxyl-terminal domain (CTD) of the largest subunit of mammalian RNA polymerase II (RNAP II) consists of 52 repeats of a consensus heptapeptide and is subject to phosphorylation and dephosphorylation events during each round of transcription. RNAP II activity is regulated during the cell cycle and cell cycledependend changes in RNAP II activity correlate well with CTD phosphorylation. In addition, global changes in the CTD phosphorylation status are observed in response to mitogenic or cytostatic signals such as growth factors, mitogens and DNA-damaging agents. Several CTD kinases are members of the cyclindependent kinase (CDK) superfamily and associate with transcription initiation complexes. Other CTD kinases implicated in cell cycle regulation include the mitogen-activated protein kinases ERK-1/2 and the c-Abl tyrosine kinase. These observations suggest that reversible RNAP II CTD phosphorylation may play a key role in linking cell cycle regulatory events to coordinated changes in transcription.

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Section: Cdks Associated With the Rnap II Transcription Machinerymentioning

confidence: 99%

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

Oelgeschläger

2002

Journal Cellular Physiology

128

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“…12,13 The N-terminal portion of AF4 family members binds to the CDK9/CCNT1 heterodimer, 14 which resembles the positive transcription elongation factor b (P-TEFb). 15 P-TEFb phosphorylates serine 2 residues within heptameric repeats of the carboxy-terminal domain (CTD) of RNA polymerase (pol) II. This leads to transcriptional elongation and allows binding of additional factors involved in RNA splicing and transcriptional termination.…”

Section: Introductionmentioning

confidence: 99%

The leukemogenic AF4–MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

et al. 2010

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Expression of the AF4-MLL fusion protein in murine hematopoietic progenitor/stem cells results in the development of proB acute lymphoblastic leukemia. In this study, we affinity purified the AF4-MLL and AF4 protein complexes to elucidate their function. We observed that the AF4 complex consists of 11 binding partners and exhibits positive transcription elongation factor b (P-TEFb)-mediated activation of promoter-arrested RNA polymerase (pol) II in conjunction with several chromatin-modifying activities. In contrast, the AF4-MLL complex consists of at least 16 constituents including P-TEFb kinase, H3K4 me3 and H3K79 me3 histone methyltransferases (HMT), a protein arginine N-methyltransferase and a histone acetyltransferase. These findings suggest that the AF4-MLL protein disturbs the fine-tuned activation cycle of promoter-arrested RNA Pol II and causes altered histone methylation signatures. Thus, we propose that these two processes are key to trigger cellular reprogramming that leads to the onset of acute leukemia.

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“…All these events convert promoter-proximal arrested RNA polymerase II into elongating polymerase. 21 The SET-domain complex and the associated histone methyltransferases DOT1L and CARM1 subsequently modify specific arginine and lysine residues of histone H3. This leads to activated chromatin and enhanced transcription.…”

Section: Introductionmentioning

confidence: 99%

The heterodimerization domains of MLL—FYRN and FYRC—are potential target structures in t(4;11) leukemia

et al. 2011

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The chromosomal translocation t(4;11)(q21;q23) is a frequent genetic aberration of the mixed lineage leukemia (MLL) gene, predominantly associated with high-risk acute lymphoblastic leukemia (ALL) in pediatric patients. Previous studies demonstrated that mice transplanted with hematopoietic cells expressing the AF4-MLL fusion protein develop proB ALL. The AF4-MLL oncoprotein becomes activated by Taspase1-mediated hydrolysis, which subsequently leads to a heterodimer of the cleavage products AF4-MLL . N and MLL . C. This proteinprotein interaction is due to the FYRN and FYRC interaction domains present in both protein fragments. Heterodimerization subsequently induces high-molecular-weight protein complex formation that is protected against SIAH1/2-mediated polyubiquitinylation. Here, we attempted to selectively block this initial heterodimerization step, aiming to prevent the oncogenic activation of the AF4-MLL multiprotein complex. The minimal interaction interface was experimentally defined first in a bacterial two-hybrid system, and then in mammalian cells by using a biosensor assay. Expression of the FYRC domain, or smaller portions thereof, resulted in the inhibition of heterodimer formation, and blocked AF4-MLL multiprotein complex formation with subsequent destruction of the AF4-MLL oncoprotein. Thus, it is in principle possible to specifically target the AF4-MLL protein. This knowledge can now be exploited to design inhibitory decoys in order to destroy the AF4-MLL oncoprotein.

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Purification of P-TEFb, a Transcription Factor Required for the Transition into Productive Elongation

Cited by 480 publications

References 30 publications

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

The leukemogenic AF4–MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

The heterodimerization domains of MLL—FYRN and FYRC—are potential target structures in t(4;11) leukemia

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