Role of the hinge region of glucocorticoid receptor for HEXIM1-mediated transcriptional repression.
We previously reported that HEXIM1 (hexamethylene bisacetamide-inducible protein 1), which suppresses transcription elongation via sequestration of positive transcription elongation factor b (P-TEFb) using 7SK RNA as a scaffold, directly associates with glucocorticoid receptor (GR) to suppress glucocorticoid-inducible gene activation. Here, we revealed that the hinge region of GR is essential for its interaction with HEXIM1, and that oxosteroid receptors including GR show sequence homology in their hinge region and interact with HEXIM1, whereas the other members of nuclear receptors do not. We also showed that HEXIM1 suppresses GR-mediated transcription in two ways: sequestration of P-TEFb by HEXIM1 and direct interaction between GR and HEXIM1. In contrast, peroxisome proliferator-activated receptor gamma-dependent gene expression is negatively modulated by HEXIM1 solely via sequestration of P-TEFb. We, therefore, conclude that HEXIM1 may act as a gene-selective transcriptional regulator via direct interaction with certain transcriptional regulators including GR and contribute to fine-tuning of, for example, glucocorticoid-mediated biological responses.
Yoshikawa
Noritada
N
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai Minato-ku, Tokyo 108-8639, Japan.
Shimizu
Noriaki
N
Sano
Motoaki
M
Ohnuma
Kei
K
Iwata
Satoshi
S
Hosono
Osamu
O
Fukuda
Keiichi
K
Morimoto
Chikao
C
Tanaka
Hirotoshi
H
D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D007664:Ketosteroids / Q000378:metabolism; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C476123:HEXIM1 protein, human; D007664:Ketosteroids; D047495:PPAR gamma; D016601:RNA-Binding Proteins; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D042925:Positive Transcriptional Elongation Factor B