TY - JOUR
T1 - The book of opposites
T2 - The role of the nuclear receptor co-regulators in the suppression of epidermal genes by retinoic acid and thyroid hormone receptors
AU - Jho, Sang H.
AU - Vouthounis, Constantinos
AU - Lee, Brian
AU - Stojadinovic, Olivera
AU - Im, Mark J.
AU - Brem, Harold
AU - Merchant, Ankit
AU - Chau, Katherine
AU - Tomic-Canic, Marjana
N1 - Funding Information:
Our research is supported by the National Institutes of Health grants AR45974, NR08029, DK59424, T3207190, and the American Diabetes Association.
PY - 2005/5
Y1 - 2005/5
N2 - Transcriptional regulation by nuclear receptors occurs through complex interactions that involve DNA response elements, co-activators/co-repressors, and histone modifying enzymes. Very little is known about how molecular interplay of these components may determine tissue specificity of hormone action. We have shown previously that retinoic acid (RA) and thyroid hormone (T3) repress transcription of a specific group of epidermal keratin genes through a novel mechanism that utilizes receptors homodimers. In this paper, we have analyzed the epidermal specificity of RA/T3 action by testing the role of co-repressors and co-activators in regulation of epidermal genes. Using transient co-transfections, northern blots, antisense oligonucleotides, and a histone deacetylase (HDAC) inhibitor, trichostatin A, we found that in the context of specific keratin RE (KRE), co-activators and histone acetylase become co-repressors of the RA/T3 receptors in the presence of their respective ligands. Conversely, co-repressors and HDAC become co-activators of unliganded T3Rα. The receptor-co-activator interaction is intact and occurs through the NR-box. Therefore, the role of co-activator is to associate with liganded receptors whereas the KRE-receptor interaction determines specific transcriptional signal, in this case repression. This novel molecular mechanism of transcriptional repression conveys how RA and T3 target specific groups of epidermal genes, thus exerting intrinsic tissue specificity.
AB - Transcriptional regulation by nuclear receptors occurs through complex interactions that involve DNA response elements, co-activators/co-repressors, and histone modifying enzymes. Very little is known about how molecular interplay of these components may determine tissue specificity of hormone action. We have shown previously that retinoic acid (RA) and thyroid hormone (T3) repress transcription of a specific group of epidermal keratin genes through a novel mechanism that utilizes receptors homodimers. In this paper, we have analyzed the epidermal specificity of RA/T3 action by testing the role of co-repressors and co-activators in regulation of epidermal genes. Using transient co-transfections, northern blots, antisense oligonucleotides, and a histone deacetylase (HDAC) inhibitor, trichostatin A, we found that in the context of specific keratin RE (KRE), co-activators and histone acetylase become co-repressors of the RA/T3 receptors in the presence of their respective ligands. Conversely, co-repressors and HDAC become co-activators of unliganded T3Rα. The receptor-co-activator interaction is intact and occurs through the NR-box. Therefore, the role of co-activator is to associate with liganded receptors whereas the KRE-receptor interaction determines specific transcriptional signal, in this case repression. This novel molecular mechanism of transcriptional repression conveys how RA and T3 target specific groups of epidermal genes, thus exerting intrinsic tissue specificity.
KW - Co-activators
KW - Co-repressors
KW - Epidermal keratin genes
KW - Retinoids
KW - Thyroid hormone
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U2 - 10.1111/j.0022-202X.2005.23691.x
DO - 10.1111/j.0022-202X.2005.23691.x
M3 - Article
C2 - 15854046
AN - SCOPUS:18244384707
VL - 124
SP - 1034
EP - 1043
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 5
ER -