Journal article
Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein (snRNP) Activates Hexamethylene Bisacetamide-inducible Protein (HEXIM1) Transcription
The Journal of biological chemistry, Vol.289(14), pp.9918-9925
04/04/2014
DOI: 10.1074/jbc.M113.539015
PMCID: PMC3975036
PMID: 24515107
Abstract
Background:
HEXIM1 inhibits P-TEFb in the 7SK snRNP.
Results:
The critical promoter driving HEXIM1 expression was identified and was found to respond to levels of free P-TEFb.
Conclusion:
HEXIM1 expression levels rise to compensate for excessive P-TEFb activity.
Significance:
Increased levels of free P-TEFb lead to induction of HEXIM1 to maintain transcriptional homeostasis.
By phosphorylating negative elongation factors and the C-terminal domain of RNA polymerase II (RNAPII), positive transcription elongation factor b (P-TEFb), which is composed of CycT1 or CycT2 and CDK9, activates eukaryotic transcription elongation. In growing cells, it is found in active and inactive forms. In the former, free P-TEFb is a potent transcriptional coactivator. In the latter, it is inhibited by HEXIM1 or HEXIM2 in the 7SK small nuclear ribonucleoprotein (snRNP), which contains, additionally, 7SK snRNA, methyl phosphate-capping enzyme (MePCE), and La-related protein 7 (LARP7). This P-TEFb equilibrium determines the state of growth and proliferation of the cell. In this study, the release of P-TEFb from the 7SK snRNP led to increased synthesis of HEXIM1 but not HEXIM2 in HeLa cells, and this occurred only from an unannotated, proximal promoter. ChIP with sequencing revealed P-TEFb-sensitive poised RNA polymerase II at this proximal but not the previously annotated distal HEXIM1 promoter. Its immediate upstream sequences were fused to luciferase reporters and were found to be responsive to many P-TEFb-releasing compounds. The superelongation complex subunits AF4/FMR2 family member 4 (AFF4) and elongation factor RNA polymerase II 2 (ELL2) were recruited to this proximal promoter after P-TEFb release and were required for its transcriptional effects. Thus, P-TEFb regulates its own equilibrium in cells, most likely to maintain optimal cellular homeostasis.
Details
- Title: Subtitle
- Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein (snRNP) Activates Hexamethylene Bisacetamide-inducible Protein (HEXIM1) Transcription
- Creators
- Pingyang Liu - From theYanhui Xiang - From theKoh Fujinaga - From theKoen Bartholomeeusen - From theKyle A Nilson - theDavid H Price - theB. Matija Peterlin - From the
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.289(14), pp.9918-9925
- DOI
- 10.1074/jbc.M113.539015
- PMID
- 24515107
- PMCID
- PMC3975036
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- U19 AI096113 / National Institutes of Health
- Alternative title
- P-TEFb Activates HEXIM1 Transcription
- Language
- English
- Date published
- 04/04/2014
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984025394302771
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