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P-TEFb- the final frontier.

Kohoutek J - Cell Div (2009)

Bottom Line: P-TEFb enables transition from abortive to productive transcription elongation by phosphorylating carboxyl-terminal domain (CTD) in RNAPII and negative transcription elongation factors.Over the years, we have learned a great deal about molecular composition of P-TEFb complexes, their assembly and their role in transcription of specific genes, but function of P-TEFb in other physiological processes was not apparent until just recently.In light of emerging discoveries connecting P-TEFb to regulation of cell cycle, development and several diseases, I would like to discuss these observations as well as future perspectives.

View Article: PubMed Central - HTML - PubMed

Affiliation: Veterinary Research Institute, Hudcova 70, 621 00 Brno, Czech Republic. Kohoutek@vri.cz.

ABSTRACT
Regulation of gene expression is essential to all aspects of physiological processes in single-cell as well as multicellular organisms. It gives ultimately cells the ability to efficiently respond to extra- and intracellular stimuli participating in cell cycle, growth, differentiation and survival. Regulation of gene expression is executed primarily at the level of transcription of specific mRNAs by RNA polymerase II (RNAPII), typically in several distinct phases. Among them, transcription elongation is positively regulated by the positive transcription elongation factor b (P-TEFb), consisting of CDK9 and cyclin T1, T2 or K. P-TEFb enables transition from abortive to productive transcription elongation by phosphorylating carboxyl-terminal domain (CTD) in RNAPII and negative transcription elongation factors. Over the years, we have learned a great deal about molecular composition of P-TEFb complexes, their assembly and their role in transcription of specific genes, but function of P-TEFb in other physiological processes was not apparent until just recently. In light of emerging discoveries connecting P-TEFb to regulation of cell cycle, development and several diseases, I would like to discuss these observations as well as future perspectives.

No MeSH data available.


Related in: MedlinePlus

Composition and assembly of P-TEFb complexes. A) 7SK snRNA contains 5'- and 3'- ends with pppG (triphosphate guanosine) and UUUU-OH (oligouridylate tail), respectively. 7SKsnRNA is recognized by MEPCE (7SK snRNA methylphosphate capping enzyme) and LARP7 (La-related protein 7). B) MEPCE methylates gamma-phosphate of its first 5'ribonucleotide, depicted by an asterisk, and LARP7 stabilizes 7SK snRNA by binding to its oligouridylate tail. Hexim1 (Hex1) homodimerizes (or heterodimerizes with Hexim2) via its coiled-coil domain in the C-terminus, but N-terminus adopts conformation which does not allow binding to P-TEFb (CDK9/Cyc). C) Binding of 7SK snRNA from 7SK snRNA/MEPCE/LARP7 complex to basic region in central part of Hexim1 triggers conformational changes of hexim dimer leading to exposition of CycT1-binding domain at the C-terminus of Hex1 and consequent binding of P-TEFb ('SMALL' complex). D) The 'LARGE' complex is formed and is stabilized due to multiple protein-protein and protein-RNA contacts within the complex. Activity of P-TEFb is inhibited in the large complex. Several stimuli have been reported to disrupt the large complex, such as UV radiation, diverse stress signals (mechanical, hypertrophic), cytokines (TNF-α, IL-6) and inhibitors (Actinomycin D, DRB).
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Figure 1: Composition and assembly of P-TEFb complexes. A) 7SK snRNA contains 5'- and 3'- ends with pppG (triphosphate guanosine) and UUUU-OH (oligouridylate tail), respectively. 7SKsnRNA is recognized by MEPCE (7SK snRNA methylphosphate capping enzyme) and LARP7 (La-related protein 7). B) MEPCE methylates gamma-phosphate of its first 5'ribonucleotide, depicted by an asterisk, and LARP7 stabilizes 7SK snRNA by binding to its oligouridylate tail. Hexim1 (Hex1) homodimerizes (or heterodimerizes with Hexim2) via its coiled-coil domain in the C-terminus, but N-terminus adopts conformation which does not allow binding to P-TEFb (CDK9/Cyc). C) Binding of 7SK snRNA from 7SK snRNA/MEPCE/LARP7 complex to basic region in central part of Hexim1 triggers conformational changes of hexim dimer leading to exposition of CycT1-binding domain at the C-terminus of Hex1 and consequent binding of P-TEFb ('SMALL' complex). D) The 'LARGE' complex is formed and is stabilized due to multiple protein-protein and protein-RNA contacts within the complex. Activity of P-TEFb is inhibited in the large complex. Several stimuli have been reported to disrupt the large complex, such as UV radiation, diverse stress signals (mechanical, hypertrophic), cytokines (TNF-α, IL-6) and inhibitors (Actinomycin D, DRB).

Mentions: Importantly, studies of biology of active complex led to identification of bromodomain protein 4 (Brd4), a major binding partner of P-TEFb when 7SK snRNA along with Hexim1/2 are displaced from P-TEFb [57,58]. Brd4 binds to acetylated histones and might be therefore targeting P-TEFb to actively transcribed genes if there is no specific factor recruiting P-TEFb to these genes [59]. Therefore, P-TEFb is typically present in two distinct complexes in most cell types. Heterodimer of CDK9/cyclin represents active P-TEFb and is here referred to as a 'small' complex of P-TEFb, irrespective of Brd4 binding (Figure 1). Whereas, cooperative binding of P-TEFb/cyclin/7SK snRNA/Hexim1 or 2/MEPCE/LARP7 identifies an inactive P-TEFb form, also recognized as 'large' complex of P-TEFb (Figure 1). Application of stress stimuli, UV radiation, cytokine treatment, chemical compounds, etc. on cells leads to dissociation of P-TEFb from Hexim1/2 and 7SK snRNA/MEPCE/LARP7 (Figure 1).


P-TEFb- the final frontier.

Kohoutek J - Cell Div (2009)

Composition and assembly of P-TEFb complexes. A) 7SK snRNA contains 5'- and 3'- ends with pppG (triphosphate guanosine) and UUUU-OH (oligouridylate tail), respectively. 7SKsnRNA is recognized by MEPCE (7SK snRNA methylphosphate capping enzyme) and LARP7 (La-related protein 7). B) MEPCE methylates gamma-phosphate of its first 5'ribonucleotide, depicted by an asterisk, and LARP7 stabilizes 7SK snRNA by binding to its oligouridylate tail. Hexim1 (Hex1) homodimerizes (or heterodimerizes with Hexim2) via its coiled-coil domain in the C-terminus, but N-terminus adopts conformation which does not allow binding to P-TEFb (CDK9/Cyc). C) Binding of 7SK snRNA from 7SK snRNA/MEPCE/LARP7 complex to basic region in central part of Hexim1 triggers conformational changes of hexim dimer leading to exposition of CycT1-binding domain at the C-terminus of Hex1 and consequent binding of P-TEFb ('SMALL' complex). D) The 'LARGE' complex is formed and is stabilized due to multiple protein-protein and protein-RNA contacts within the complex. Activity of P-TEFb is inhibited in the large complex. Several stimuli have been reported to disrupt the large complex, such as UV radiation, diverse stress signals (mechanical, hypertrophic), cytokines (TNF-α, IL-6) and inhibitors (Actinomycin D, DRB).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2748068&req=5

Figure 1: Composition and assembly of P-TEFb complexes. A) 7SK snRNA contains 5'- and 3'- ends with pppG (triphosphate guanosine) and UUUU-OH (oligouridylate tail), respectively. 7SKsnRNA is recognized by MEPCE (7SK snRNA methylphosphate capping enzyme) and LARP7 (La-related protein 7). B) MEPCE methylates gamma-phosphate of its first 5'ribonucleotide, depicted by an asterisk, and LARP7 stabilizes 7SK snRNA by binding to its oligouridylate tail. Hexim1 (Hex1) homodimerizes (or heterodimerizes with Hexim2) via its coiled-coil domain in the C-terminus, but N-terminus adopts conformation which does not allow binding to P-TEFb (CDK9/Cyc). C) Binding of 7SK snRNA from 7SK snRNA/MEPCE/LARP7 complex to basic region in central part of Hexim1 triggers conformational changes of hexim dimer leading to exposition of CycT1-binding domain at the C-terminus of Hex1 and consequent binding of P-TEFb ('SMALL' complex). D) The 'LARGE' complex is formed and is stabilized due to multiple protein-protein and protein-RNA contacts within the complex. Activity of P-TEFb is inhibited in the large complex. Several stimuli have been reported to disrupt the large complex, such as UV radiation, diverse stress signals (mechanical, hypertrophic), cytokines (TNF-α, IL-6) and inhibitors (Actinomycin D, DRB).
Mentions: Importantly, studies of biology of active complex led to identification of bromodomain protein 4 (Brd4), a major binding partner of P-TEFb when 7SK snRNA along with Hexim1/2 are displaced from P-TEFb [57,58]. Brd4 binds to acetylated histones and might be therefore targeting P-TEFb to actively transcribed genes if there is no specific factor recruiting P-TEFb to these genes [59]. Therefore, P-TEFb is typically present in two distinct complexes in most cell types. Heterodimer of CDK9/cyclin represents active P-TEFb and is here referred to as a 'small' complex of P-TEFb, irrespective of Brd4 binding (Figure 1). Whereas, cooperative binding of P-TEFb/cyclin/7SK snRNA/Hexim1 or 2/MEPCE/LARP7 identifies an inactive P-TEFb form, also recognized as 'large' complex of P-TEFb (Figure 1). Application of stress stimuli, UV radiation, cytokine treatment, chemical compounds, etc. on cells leads to dissociation of P-TEFb from Hexim1/2 and 7SK snRNA/MEPCE/LARP7 (Figure 1).

Bottom Line: P-TEFb enables transition from abortive to productive transcription elongation by phosphorylating carboxyl-terminal domain (CTD) in RNAPII and negative transcription elongation factors.Over the years, we have learned a great deal about molecular composition of P-TEFb complexes, their assembly and their role in transcription of specific genes, but function of P-TEFb in other physiological processes was not apparent until just recently.In light of emerging discoveries connecting P-TEFb to regulation of cell cycle, development and several diseases, I would like to discuss these observations as well as future perspectives.

View Article: PubMed Central - HTML - PubMed

Affiliation: Veterinary Research Institute, Hudcova 70, 621 00 Brno, Czech Republic. Kohoutek@vri.cz.

ABSTRACT
Regulation of gene expression is essential to all aspects of physiological processes in single-cell as well as multicellular organisms. It gives ultimately cells the ability to efficiently respond to extra- and intracellular stimuli participating in cell cycle, growth, differentiation and survival. Regulation of gene expression is executed primarily at the level of transcription of specific mRNAs by RNA polymerase II (RNAPII), typically in several distinct phases. Among them, transcription elongation is positively regulated by the positive transcription elongation factor b (P-TEFb), consisting of CDK9 and cyclin T1, T2 or K. P-TEFb enables transition from abortive to productive transcription elongation by phosphorylating carboxyl-terminal domain (CTD) in RNAPII and negative transcription elongation factors. Over the years, we have learned a great deal about molecular composition of P-TEFb complexes, their assembly and their role in transcription of specific genes, but function of P-TEFb in other physiological processes was not apparent until just recently. In light of emerging discoveries connecting P-TEFb to regulation of cell cycle, development and several diseases, I would like to discuss these observations as well as future perspectives.

No MeSH data available.


Related in: MedlinePlus