| RRC ID |
1485
|
| Author |
Shimizu N, Ouchida R, Yoshikawa N, Hisada T, Watanabe H, Okamoto K, Kusuhara M, Handa H, Morimoto C, Tanaka H.
|
| Title |
HEXIM1 forms a transcriptionally abortive complex with glucocorticoid receptor without involving 7SK RNA and positive transcription elongation factor b.
|
| Journal |
Proc Natl Acad Sci U S A
|
| Abstract |
The HEXIM1 protein has been shown to form a protein-RNA complex composed of 7SK small nuclear RNA and positive transcription elongation factor b (P-TEFb), which is composed of cyclin-dependent kinase 9 (CDK9) and cyclin T1, and to inhibit the kinase activity of CDK9, thereby suppressing RNA polymerase II-dependent transcriptional elongation. Here, we biochemically demonstrate that HEXIM1 forms a distinct complex with glucocorticoid receptor (GR) without RNA, CDK9, or cyclin T1. HEXIM1, through its arginine-rich nuclear localization signal, directly associates with the ligand-binding domain of GR. Introduction of HEXIM1 short interfering RNA and adenovirus-mediated exogenous expression of HEXIM1 positively and negatively modulated glucocorticoid-responsive gene activation, respectively. In the nucleus, HEXIM1 was shown to localize in a distinct compartment from that of the p160 coactivator transcriptional intermediary factor 2. Overexpression of HEXIM1 decreased ligand-dependent association between GR and transcriptional intermediary factor 2. Antisense-mediated disruption of 7SK blunted the negative effect of HEXIM1 on arylhydrocarbon receptor-dependent transcription but not on GR-mediated one, indicating that a class of transcription factors are direct targets of HEXIM1. These results indicate that HEXIM1 has dual roles in transcriptional regulation: inhibition of transcriptional elongation dependent on 7SK RNA and positive transcription elongation factor b and interference with the sequence-specific transcription factor GR via a direct protein-protein interaction. Moreover, the fact that the central nuclear localization signal of HEXIM1 is essential for both of these actions may argue the crosstalk of these functions.
|
| Volume |
102(24)
|
| Pages |
8555-60
|
| Published |
2005-6-14
|
| DOI |
10.1073/pnas.0409863102
|
| PII |
0409863102
|
| PMID |
15941832
|
| PMC |
PMC1150813
|
| MeSH |
Animals
COS Cells
Chlorocebus aethiops
Fluorescent Antibody Technique, Indirect
Gene Expression Regulation*
Glutathione Transferase
HeLa Cells
Humans
Immunoprecipitation
Luciferases
Mass Spectrometry
Multiprotein Complexes / metabolism*
Nuclear Receptor Coactivator 2
Oligonucleotide Array Sequence Analysis
Protein Binding
Protein Structure, Tertiary
RNA, Small Interfering / genetics
RNA-Binding Proteins / metabolism*
Receptors, Glucocorticoid / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / metabolism
Transcriptional Activation
Transfection
|
| IF |
9.412
|
| Times Cited |
34
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Human and Animal Cells |
HeLa(RCB0007)
COS-7(RCB0539)
Hep G2 |
