PMID- 25056306
OWN - NLM
STAT- MEDLINE
DCOM- 20141104
LR  - 20211021
IS  - 1362-4962 (Electronic)
IS  - 0305-1048 (Print)
IS  - 0305-1048 (Linking)
VI  - 42
IP  - 14
DP  - 2014 Aug
TI  - Acute hypoxia affects P-TEFb through HDAC3 and HEXIM1-dependent mechanism to 
      promote gene-specific transcriptional repression.
PG  - 8954-69
LID - 10.1093/nar/gku611 [doi]
AB  - Hypoxia is associated with a variety of physiological and pathological conditions 
      and elicits specific transcriptional responses. The elongation competence of RNA 
      Polymerase II is regulated by the positive transcription elongation factor b 
      (P-TEFb)-dependent phosphorylation of Ser2 residues on its C-terminal domain. 
      Here, we report that hypoxia inhibits transcription at the level of elongation. 
      The mechanism involves enhanced formation of inactive complex of P-TEFb with its 
      inhibitor HEXIM1 in an HDAC3-dependent manner. Microarray transcriptome profiling 
      of hypoxia primary response genes identified  approximately 79% of these genes being 
      HEXIM1-dependent. Hypoxic repression of P-TEFb was associated with reduced 
      acetylation of its Cdk9 and Cyclin T1 subunits. Hypoxia caused nuclear 
      translocation and co-localization of the Cdk9 and HDAC3/N-CoR repressor complex. 
      We demonstrated that the described mechanism is involved in hypoxic repression of 
      the monocyte chemoattractant protein-1 (MCP-1) gene. Thus, HEXIM1 and 
      HDAC-dependent deacetylation of Cdk9 and Cyclin T1 in response to hypoxia 
      signalling alters the P-TEFb functional equilibrium, resulting in repression of 
      transcription.
CI  - (c) The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic 
      Acids Research.
FAU - Safronova, Olga S
AU  - Safronova OS
AD  - Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical 
      and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan Global 
      Center of Excellence Program, International Research Center for Molecular Science 
      in Tooth and Bone Diseases, Tokyo Medical and Dental University, 1-5-45, Yushima, 
      Bunkyo-ku, Tokyo 113-8549, Japan.
FAU - Nakahama, Ken-Ichi
AU  - Nakahama K
AD  - Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical 
      and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
FAU - Morita, Ikuo
AU  - Morita I
AD  - Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical 
      and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan Global 
      Center of Excellence Program, International Research Center for Molecular Science 
      in Tooth and Bone Diseases, Tokyo Medical and Dental University, 1-5-45, Yushima, 
      Bunkyo-ku, Tokyo 113-8549, Japan morita.cell@tmd.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140723
PL  - England
TA  - Nucleic Acids Res
JT  - Nucleic acids research
JID - 0411011
RN  - 0 (Chemokine CCL2)
RN  - 0 (Cyclin T)
RN  - 0 (HEXIM1 protein, human)
RN  - 0 (Nuclear Receptor Co-Repressor 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Transcription Factors)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.- (Positive Transcriptional Elongation Factor B)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 9)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - EC 3.5.1.98 (histone deacetylase 3)
SB  - IM
MH  - Acetylation
MH  - Active Transport, Cell Nucleus
MH  - Cell Hypoxia
MH  - Cell Nucleus/enzymology
MH  - Chemokine CCL2/biosynthesis/genetics
MH  - Cyclin T/metabolism
MH  - Cyclin-Dependent Kinase 9/metabolism
MH  - *Gene Expression Regulation
MH  - HeLa Cells
MH  - Histone Deacetylases/*metabolism/physiology
MH  - Humans
MH  - Nuclear Receptor Co-Repressor 1/metabolism
MH  - Phosphorylation
MH  - Positive Transcriptional Elongation Factor B/chemistry/*metabolism
MH  - RNA, Messenger/biosynthesis
MH  - RNA-Binding Proteins/*physiology
MH  - Serine/metabolism
MH  - *Transcription Elongation, Genetic
MH  - Transcription Factors
MH  - Transcriptome
PMC - PMC4132729
EDAT- 2014/07/25 06:00
MHDA- 2014/11/05 06:00
PMCR- 2014/07/23
CRDT- 2014/07/25 06:00
PHST- 2014/07/25 06:00 [entrez]
PHST- 2014/07/25 06:00 [pubmed]
PHST- 2014/11/05 06:00 [medline]
PHST- 2014/07/23 00:00 [pmc-release]
AID - gku611 [pii]
AID - 10.1093/nar/gku611 [doi]
PST - ppublish
SO  - Nucleic Acids Res. 2014 Aug;42(14):8954-69. doi: 10.1093/nar/gku611. Epub 2014 
      Jul 23.