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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.


Active and inactive P-TEFb complexes. A) Active P-TEFb complexes. CDK942 (green oval) and CDK955 (orange oval) can separately bind to individual CycT1 (yellow circle), CycT2a (violet oval), CycT2b (lavender oval) and CycK (pink oval). B) Inactive P-TEFb complexes with CycT1. Only large complexes with CycT1 are presented for illustration, but the same would apply for CycT2a, CycT2b and CycK too. Complexes of 42- and CDK955 with CycT1 are presented at the left side. 'Large' complexes consisting of CDK9/CycT1 are at the right side. Hexim1/7SK snRNA (light blue oval), Hexim2/7SK snRNA (turquoise blue oval), MEPCE/LARP7 (light orange oval).
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Figure 2: Active and inactive P-TEFb complexes. A) Active P-TEFb complexes. CDK942 (green oval) and CDK955 (orange oval) can separately bind to individual CycT1 (yellow circle), CycT2a (violet oval), CycT2b (lavender oval) and CycK (pink oval). B) Inactive P-TEFb complexes with CycT1. Only large complexes with CycT1 are presented for illustration, but the same would apply for CycT2a, CycT2b and CycK too. Complexes of 42- and CDK955 with CycT1 are presented at the left side. 'Large' complexes consisting of CDK9/CycT1 are at the right side. Hexim1/7SK snRNA (light blue oval), Hexim2/7SK snRNA (turquoise blue oval), MEPCE/LARP7 (light orange oval).

Mentions: Ad 1) Usually, when we think of P-TEFb, two functional states are considered: active (small complex, typically CDK942/CycT1) and inactive (large complex, CDK942/CycT1/7SK snRNA/Hexim1/LARP7/MEPCE). One must actually revise our rather simplified view on P-TEF complexes, as proposed in several publications [36,105]. Active P-TEFb consists of CDK9 and C-type cyclin, but two forms of CDK9 exist (CDK942 and CDK955) and at least four isoforms of C-type cyclins (CycT1, CycT2a, CycT2b and CycK). By simple combinatorial math, it leaves us with 8 different complexes of active P-TEFb (Figure 2A). Taking in account the existence of Hexim1, Hexim2, 7SK snRNA, LARP7 and MEPCE, we will come to number 16 for inactive P-TEFb complexes (Figure 2B). All together there are 24 P-TEFb complexes with unique molecular surface composition. One might argue that binding of P-TEFb strictly depends on recognition capacity of cyclin boxes, histidine-rich and leucine rich regions in cyclins and substrate binding site in CDK9, but other possibilities should be considered, too. CDK9/cyclin adopts more open conformation different from CDK2/CycA providing extra molecular surfaces available for new interactions [63]. Also, other components of small or large complexes can mediate interaction with various factors. Indeed, nucleophosmin and NFkB associate with basic region of Hexim1 [45,106]. Also, estrogen and glucocorticoid receptors bind Hexim1 through its basic region [107,108]. Examples of these associations have served only to demonstrate hidden reserves of P-TEFb to interact with distinct factors.


P-TEFb- the final frontier.

Kohoutek J - Cell Div (2009)

Active and inactive P-TEFb complexes. A) Active P-TEFb complexes. CDK942 (green oval) and CDK955 (orange oval) can separately bind to individual CycT1 (yellow circle), CycT2a (violet oval), CycT2b (lavender oval) and CycK (pink oval). B) Inactive P-TEFb complexes with CycT1. Only large complexes with CycT1 are presented for illustration, but the same would apply for CycT2a, CycT2b and CycK too. Complexes of 42- and CDK955 with CycT1 are presented at the left side. 'Large' complexes consisting of CDK9/CycT1 are at the right side. Hexim1/7SK snRNA (light blue oval), Hexim2/7SK snRNA (turquoise blue oval), MEPCE/LARP7 (light orange oval).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 2: Active and inactive P-TEFb complexes. A) Active P-TEFb complexes. CDK942 (green oval) and CDK955 (orange oval) can separately bind to individual CycT1 (yellow circle), CycT2a (violet oval), CycT2b (lavender oval) and CycK (pink oval). B) Inactive P-TEFb complexes with CycT1. Only large complexes with CycT1 are presented for illustration, but the same would apply for CycT2a, CycT2b and CycK too. Complexes of 42- and CDK955 with CycT1 are presented at the left side. 'Large' complexes consisting of CDK9/CycT1 are at the right side. Hexim1/7SK snRNA (light blue oval), Hexim2/7SK snRNA (turquoise blue oval), MEPCE/LARP7 (light orange oval).
Mentions: Ad 1) Usually, when we think of P-TEFb, two functional states are considered: active (small complex, typically CDK942/CycT1) and inactive (large complex, CDK942/CycT1/7SK snRNA/Hexim1/LARP7/MEPCE). One must actually revise our rather simplified view on P-TEF complexes, as proposed in several publications [36,105]. Active P-TEFb consists of CDK9 and C-type cyclin, but two forms of CDK9 exist (CDK942 and CDK955) and at least four isoforms of C-type cyclins (CycT1, CycT2a, CycT2b and CycK). By simple combinatorial math, it leaves us with 8 different complexes of active P-TEFb (Figure 2A). Taking in account the existence of Hexim1, Hexim2, 7SK snRNA, LARP7 and MEPCE, we will come to number 16 for inactive P-TEFb complexes (Figure 2B). All together there are 24 P-TEFb complexes with unique molecular surface composition. One might argue that binding of P-TEFb strictly depends on recognition capacity of cyclin boxes, histidine-rich and leucine rich regions in cyclins and substrate binding site in CDK9, but other possibilities should be considered, too. CDK9/cyclin adopts more open conformation different from CDK2/CycA providing extra molecular surfaces available for new interactions [63]. Also, other components of small or large complexes can mediate interaction with various factors. Indeed, nucleophosmin and NFkB associate with basic region of Hexim1 [45,106]. Also, estrogen and glucocorticoid receptors bind Hexim1 through its basic region [107,108]. Examples of these associations have served only to demonstrate hidden reserves of P-TEFb to interact with distinct factors.

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.