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Thyroid Hormone, T3-Dependent Phosphorylation and Translocation of Trip230 from the Golgi Complex to the Nucleus

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Thyroid Hormone, T3-Dependent Phosphorylation and Translocation of Trip230 from the Golgi Complex to the Nucleus Proc. Natl. Acad. Sci. USA Vol. 96, pp. 4443–4448, April 1999 Cell Biology Thyroid hormone, T3-dependent phosphorylation and translocation of Trip230 from the Golgi complex to the nucleus YUMAY CHEN,PHANG-LANG CHEN,CHI-FEN CHEN,Z.DAVE SHARP, AND WEN-HWA LEE* Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245-3207 Communicated by Bert W. O’Malley, Baylor College of Medicine, Houston, TX, February 17, 1999 (received for review December 28, 1998) ABSTRACT Trip230 is a novel coactivator of the thyroid tion (5). These results concerning modulation of hormonal hormone receptor that is negatively regulated by the retino- signaling provided additional evidence of the pleiotrophic, but blastoma tumor-suppressor protein. In an examination of its overlapping, functions of retinoblastoma protein (Rb) in cel- subcellular distribution, Trip230 localized predominantly to lular proliferation, differentiation, and development (6). the vicinity of the Golgi instead of the nucleus, as other nuclear How coactivators are recruited coordinately to the activated hormone receptor coactivators. Using a series of deletion TR is unclear. One possibility is that hormones also are mutants, a critical region identified for Golgi area targeting involved in this process by modifying the receptor, their coincided with a previously defined thyroid hormone receptor- cofactors, or both. Nuclear localization is a prerequisite for binding domain of Trip230. During cell cycle progression, the nuclear hormone receptors and their cofactors to function as expression level of Trip230 is constant and a significant transcriptional regulators. Thus, translocation of these factors portion is imported into the nucleus at S phase. Within an from cytoplasm to nucleus also may be regulated. Based on hour of treating cells with T3, Trip230 immunofluorescence hormone-binding assays, it was proposed that TR is nuclear transiently colocalized with TR in prominent subnuclear regardless of ligand status (7). Although its cellular localiza- structures. T3-dependent nuclear import of Trip230 does not tion is not entirely clear, cellular partitioning of TR may be, in require new protein synthesis. Coincident with T3 treatment part, dependent on ligand binding. How compartmentalization and nuclear import, newly phosphorylated residue(s) ap- of nuclear receptors is regulated in conjunction with their peared in Trip230, suggesting that phosphorylation may be coactivators is not known. involved in its nuclear import. These findings provided a novel To study further the coactivator function of Trip230, we mechanism for the regulation of nuclear hormone transcrip- investigated its cellular partitioning in relation to TR in the tion factors by hormone-responsive phosphorylation and nu- presence or absence of thyroid hormone. Interestingly, we clear import of cytoplasmically located coactivators. found that Trip230 is localized mainly at the Golgi complex region in the cells cultured in T3-free medium. Translocation Steroid, retinoic acid, and thyroid hormone receptors function into the nucleus and colocalization with TR are T3-dependent as ligand-activated transcription factors that control multiple and correlate with phosphorylation of additional residues of biological functions, including cell proliferation, differentia- Trip230. tion, morphogenesis, programmed cell death, and metabolic homeostasis. Understanding the molecular and cellular mech- MATERIALS AND METHODS anisms underlying the ability of these receptors to regulate the transcription of specific target genes is a major challenge. In Cell Culture, Synchronization, and DNA Transfections. recent years, a number of interacting proteins have been CV1 monkey kidney cells were grown on plastic surfaces at identified that are critical for the transcriptional responses 37°C in a humidified 10% CO2-containing atmosphere in transduced by nuclear hormone receptors (reviewed in refs. 1 DMEM (GIBCO) supplemented with 10% heat-inactivated and 2). These coactivators or corepressors form multiprotein FCS (Flow Laboratories). Each 10-cm dish of cells grown to complexes to regulate the expression of hormone-responsive 60% confluence then was cultured in medium containing target genes. Different cell types may have distinct composi- charcoal-striped serum for 36 hr. In the case of hormone treatments, T3 was added to the medium to a final concen- tions of associated factors in the nuclear hormone receptor 2 complexes, individual members of which may integrate distinct tration of 10 6 M. Cyclohexamide at 10 mgyml, in addition to physiological signals (2). T3, was included in the treatment of some cells shown in Fig. How a small lipophilic molecule, such as 3,39,5-triiodo-L- 4C. At the various times indicated, cells were fixed for immu- thyronine (T3), coordinates and activates transcription of nostaining (see below) or lysed for Western blot analysis. target genes remains unclear. Thyroid hormone receptor (TR) Human bladder carcinoma cells, T24 (American Type Culture bound to positive thyroid hormone-responsive elements in the Collection, Manassas, VA), grown in DMEMy10% FCS, were absence of ligand decreases transcription. This silencing is due synchronized at G1 by density arrest as described previously to the interactions of the nuclear corepressors NcoR and (8). The transfection experiments in Fig. 3 were done with 1 3 SMRT (3, 4). Ligand-dependent activation of the TR results in 106 cells by using conventional calcium phosphateyDNA (10 removal of the corepressors that are replaced with coactivator mg) coprecipitation. Twelve hours posttransfection, the pre- complex [pCIPySRC1yNcoA-1ypCAF and CBPyp300 (re- cipitates were removed, and the cells were refed fresh medium viewed in refs. 1 and 2)]. One such coactivator, Trip230, binds and observed under a fluorescence microscope (Nikon) 36 hr TR in a T3-dependent manner and potentiates transcription of posttransfection. T3-activated receptor (5). Trip230 originally was identified as Immunoprecipitation and Western Blot Analysis. Cells re- a protein that binds the retinoblastoma protein, which, inter- suspended in Lysis 250 buffer were subjected to three freezey estingly, can down-regulate Trip230yTR-mediated transcrip- Abbreviations: Rb, retinoblastoma protein; TR and TRb, thyroid 9 The publication costs of this article were defrayed in part by page charge hormone receptor; T3, 3,3 ,5-triiodo-L-thyronine; GFP, green fluo- rescent protein. payment. This article must therefore be hereby marked ‘‘advertisement’’ in *To whom reprint requests should be addressed at: Department of accordance with 18 U.S.C. §1734 solely to indicate this fact. Molecular Medicine, Institute of Biotechnology, 15355 Lambda PNAS is available online at www.pnas.org. Drive, San Antonio, TX 78245-3207. e-mail: [email protected]. 4443 Downloaded by guest on October 3, 2021 4444 Cell Biology: Chen et al. Proc. Natl. Acad. Sci. USA 96 (1999) thaw cycles (liquid nitrogeny37°C) and then centrifuged at thyroid hormone (T3)-mediated transcription (5). Because T3 14,000 rpm for 2 min at room temperature. The supernatants is important for growth regulation, especially through the were used for immunoprecipitation as described (9). Briefly, insulin-like growth factor I pathway (12, 13), we were inter- mouse polyclonal anti-C5 (Trip230) antisera (1 ml) were added ested in determining whether Trip230 expression is cell cycle- to each supernatant. After a 1-hr incubation, protein-A Sepha- regulated. Bladder carcinoma T24 cells were arrested at G1 by rose beads were added and incubation continued for another contact inhibition at high density and then released to enter hour. Beads then were collected, washed five times with lysis the cell cycle by plating at low density (8, 14). M phase cells buffer containing 250 mM NaCl, and then boiled in SDS- were enriched by an additional treatment with nocadozol. Cells loading buffer for immunoblot analysis as described (8). were harvested at different stages of cell cycle, and protein Immunostaining. Cells grown on coverslips in tissue culture expression was analyzed by Western blotting by using specific dishes were washed in PBS and fixed for 30 min in 4% antibodies. As shown in Fig. 1A, the amount of Trip230 is not formaldehyde in PBS with 0.5% Triton X-100. After treating altered during the cell cycle. Rb, whose expression and phos- with 0.05% Saponin in water for 30 min and washing exten- phorylation is cell cycle-regulated, served as a marker for the sively with PBS, the cells were blocked in PBS containing 10% cell cycle stages as described previously (14). p84, a nuclear normal goat serum. An overnight incubation with antibody matrix protein whose expression is not cell cycle-regulated, diluted in 10% goat serum at 4°C was followed by three washes served as loading control. This result suggests that the regu- and then by another 1-hr incubation with fluorochrome- lation of Trip230 may be at the posttranslational level. conjugated secondary antibody. Colocalization of Trip230 and Cell Cycle Dynamics of Trip230 Cellular Partitioning. Be- mannosidase II or TR was performed by using a polyclonal cause Trip230 is proposed to be a coactivator for TR (5), a (mouse) anti-C5 antibody mixed with polyclonal (rabbit) anti- transcription factor that functions in the nucleus, we were ManII antisera (10) or polyclonal (rabbit) anti-TR antibody interested in determining the cellular partitioning of Trip230 (TR-b117;
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