Geldanamycin, an inhibitor of Hsp90, Blocks cytoplasmic retention of progesterone receptors and glucocorticoid receptors via their respective ligand binding domains
Journal Title: The AAPS Journal - Year 2006, Vol 8, Issue 4
Abstract
Steroid hormone receptors (SHRs), such as glucocorticoid receptors (GR) and progesterone receptors (PR), are shuttling proteins that undergo continuous nuclear import and export. Various mechanisms have been proposed to explain the localization of SHRs. It has been suggested that the ligand-binding domain (LBD) of SHRs is important in determining the subcellular localization. We have studied the localization of GR-LBD and PR-LBD alone, as well as of full-length GR and PR in the presence of geldanamycin (GA), a benzoquinoid ansamycin that specifically inhibits heat shock protection (Hsp90), using transient transfections and fluorescent microscopy. Our studies have indicated that GR-LBD and PR-LBD are retained in the cytoplasm via interaction with Hsp90. It was observed that in the unliganded state, treatment with GA translocates these LBDs to the nucleus. Similar results were obtained for full-length PR and GR. Additionally, it was found that after ligand induction, GA accelerated reexport of SHRs after ligand washout, implicating Hsp90 in nuclear retention of SHRs in the washout state. We also propose that a recently found “export” signal present in the LBD of SHRs is involved in interactions with Hsp90 and hence cytoplasmic retention of these receptors. After ligand induction, Hsp90 also may play a role in nuclear retention of SHRs following hormone washout.
Authors and Affiliations
Mudit Kakar, Charu Kanwal, J. Rian Davis, Henan Li, Carol S. Lim
Keywords
Related Articles
- EP ID EP681828
- DOI 10.1208/aapsj080481
- Views 68
- Downloads 0
Topical Ocular Delivery of NSAIDs
In ocular tissue, arachidonic acid is metabolized by cyclooxygenase to prostaglandins which are the most important lipid derived mediators of inflammation. Presently nonsteroidal anti-inflammatory drugs (NSAIDs) which ar...
CNS Delivery Via Adsorptive Transcytosis
Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding an...
Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs
Interest in cannabinoid pharmacology increased dramatically upon the identification of the first cannabinoid receptor (CB1) in 1998 and continues to expand as additional endocannabinoids and cannabinoid receptors are dis...
The back-step method—Method for obtaining unbiased population parameter estimates for ordered categorical data
A significant bias in parameters, estimated with the proportional odds model using the software NONMEM, has been reported. Typically, this bias occurs with ordered categorical data, when most of the observations are foun...
Peptide Amphiphile Micelles Self-Adjuvant Group A Streptococcal Vaccination
Delivery system design and adjuvant development are crucially important areas of research for improving vaccines. Peptide amphiphile micelles are a class of biomaterials that have the unique potential to function as both...