The Book of Opposites: The Role of the Nuclear Receptor Co-regulators in the Suppression of Epidermal Genes by Retinoic Acid and Thyroid Hormone Receptors

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

Novel Mechanism of Steroid Action in Skin through Glucocorticoid Receptor Monomers

Glucocorticoids (GCs), important regulators of epidermal growth, differentiation, and homeostasis, are used extensively in the treatment of skin diseases. Using keratin gene expression as a paradigm of epidermal physiology and pathology, we have developed a model system to study the molecular mechanism of GCs action in skin. Here we describe a novel mechanism of suppression of transcription by the glucocorticoid receptor (GR) that represents an example of customizing a device for transcriptional regulation to target a specific group of genes within the target tissue, in our case, epidermis. We have shown that GCs repress the expression of the basal-cell-specific keratins K5 and K14 and disease-associated keratins K6, K16, and K17 but not the differentiation-specific keratins K3 and K10 or the simple epithelium-specific keratins K8, K18, and K19. We have identified the negative recognition elements (nGREs) in all five regulated keratin gene promoters. Detailed footprinting revealed that the function of nGREs is to instruct the GR to bind as four monomers. Furthermore, using cotransfection and antisense technology we have found that, unlike SRC-1 and GRIP-1, which are not involved in the GR complex that suppresses keratin genes, histone acetyltransferase and CBP are. In addition, we have found that GR, independently from GREs, blocks the induction of keratin gene expression by AP1. We conclude that GR suppresses keratin gene expression through two independent mechanisms: directly, through interactions of keratin nGREs with four GR monomers, as well as indirectly, by blocking the AP1 induction of keratin gene expression

Modified transcorporeal anterior cervical microforaminotomy for cervical radiculopathy: a technical note and early results

A prospective analysis of the first twenty patients operated for cervical radiculopathy by a new modification of transcorporeal anterior cervical foraminotomy technique. To evaluate early results of a functional disc surgery in which decompression for the cervical radiculopathy is done by drilling a hole in the upper vertebral body and most of the disc tissue is preserved. Earlier approaches to cervical disc surgery either advocated simple discectomy or discectomy with fusion, ultimately leading to loss of motion segment. Posterior foraminotomy does not address the more common anterior lesion. Twenty patients suffering from cervical radiculopathy not responding to conservative treatment were chosen for the new technique. Upper vertebral transcorporeal foraminotomy was performed with the modified technique in all the patients. All the patients experienced immediate/early relief of symptoms. No complications of vertebral artery injury, Horner’s syndrome or recurrent laryngeal nerve palsy were noted. Modified transcorporeal anterior cervical microforaminotomy is an effective treatment for cervical radiculopathy. It avoids unnecessary violation of the disc space and much of the bony stabilizers of the cervical spine. Short-term results of this technique are quite encouraging. Longer-term analysis can help in outlining the true benefits of this technique