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The Presence of Both the Amino- and Carboxyl-Terminal Domains in the AR Is Essential for the Completion of a Transcriptionally Active Form with Coactivators and Intranuclear Compartmentalization Common to the Steroid Hormone Receptors: A Three-Dimensional Imaging Study

Departments of Medicine and Bioregulatory Science (M.S., K.G., A.T., T.Y., H.N.) and Geriatric Medicine (R.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Center for Tsukuba Advanced Research Alliance (A.F.), Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; and CREST (Core Research for Evolutional Science and Technology), JST (Japan Science and Technology) (R.T., K.G., T.Y., H.N.), Kawaguchi 332-0012 Japan

Address all correspondence and requests for reprints to: Hajime Nawata, M.D., Ph.D., Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: nawata{at}intmed3.med.kyushu-u.ac.jp.

To clarify the physiological significance of the intranuclear speckled distribution, or foci formation, of liganded steroid receptors, the subnuclear distribution of green (GFP), yellow (YFP), and cyan (CFP) fluorescent protein-tagged receptors and coactivators was investigated. The foci formation of 5-dihydrotestosterone (DHT)-bound AR-GFP in COS7 cells was abolished by the cotransfection of a CBP (118–2393) fragment eliciting a dominant negative effect on the transactivation capacity of the AR. The N-terminal AR fragment (AR-AF-1-YFP), which has a strong constitutive transactivation function, formed foci without DHT, whereas the C-terminal AR fragment (AR-AF-2-CFP), which has a quite low transactivation function, was distributed homogeneously even in the presence of DHT. The reporter gene assay showed a synergism between the transactivation functions of AR-AF-1 and AR-AF-2. This synergism was not reflected by the above two-dimensional imaging. In contrast, a three-dimensional imaging method clearly showed a difference in the intranuclear spatial distribution. The DHT-bound wild-type AR-GFP alone or AR-AF-1-YFP plus DHT-bound AR-AF-2-CFP was distributed as approximately 300 discrete spots in one nucleus, whereas AR-AF-1-YFP alone was distributed as one volume in a reticular pattern. Furthermore, not only AR but also the glucocorticoid receptor-YFP, ER -GFP, and YFP-tagged SRC-1, TIF2, and CBP were found to be accumulated in identical spots in the presence of ligand. All of the above results indicate that CBP is one of the factors essential for foci formation of the AR, and may propose the hypothesis that transcriptionally activated steroid receptors, regardless of the type of receptor, are transferred to common compartments (foci) and form a complex with coactivators, and this process is essential to full transactivation.

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