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© The Rockefeller University Press, 0021-9525/2001//1099 $5.00
The Journal of Cell Biology, Volume 152, Number 5, , 2001 1099-1106

The Transcription Coactivator Cbp Is a Dynamic Component of the Promyelocytic Leukemia Nuclear Body

^a Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta T2N 4N1, Canada
^b Cross Cancer Institute, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada
Department of Cell Biology and Anatomy, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB, T2N 4N1 Canada.(403) 270-0737(403) 220-3025

bazett{at}ucalgary.ca

The transcription coactivator and histone acetyltransferase CAMP response element–binding protein (CBP) has been demonstrated to accumulate in promyelocytic leukemia (PML) bodies. We show that this accumulation is cell type specific. In cells where CBP does not normally accumulate in PML bodies, it can be induced to accumulate in PML bodies through overexpression of either CBP or Pml, but not Sp100. Using fluorescence recovery after photobleaching, we demonstrate that CBP moves rapidly into and out of PML bodies. In contrast, Pml and Sp100 are relatively immobile in the nucleoplasm and within PML nuclear bodies. They possess the characteristics expected of proteins that would play a structural role in the integrity of these subnuclear domains. Our results are consistent with CBP being a dynamic component of PML bodies and that the steady-state level in these structures can be modulated by Pml.

Key Words: nuclear structure • promyelocytic leukemia • PML body • ND10 • fluorescence recovery after photobleaching

© 2001 The Rockefeller University Press

	Introduction

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The cell nucleus is highly organized and contains well-defined subdomains. In contrast to cytoplasmic organelles, the different subnuclear compartments are not separated from the surrounding by a lipid bilayer. Instead, subnuclear structures are delineated by an accumulation of specific proteins within a defined volume and retain a typical size, shape, and number under normal growth conditions. It is not known how such compartments are formed, and it remains to be shown whether an underlying structural framework locally concentrates the components or whether the local accumulation results from random aggregations of rapidly diffusing components (Pederson 2000). Specific proteins have been shown to associate and dissociate rapidly between the nucleoplasm and subnuclear compartments (Kruhlak et al. 2000; Phair and Misteli 2000), but how such mobile proteins are concentrated within these compartments is not known.

The promyelocytic leukemia (PML) nuclear body, a nuclear matrix–associated structure of 250–500 nm in diameter, is present in the nucleus of most cell lines (Ascoli and Maul 1991; Stuurman et al. 1992). The first biochemical component of PML nuclear bodies to be identified was the Sp100 nuclear matrix–associated protein, an autoantigen in some patients with primary biliary cirrhosis (Szostecki et al. 1990). This protein may transactivate a variety of promoters (Guldner et al. 1992; Xie et al. 1993). The PML gene product, Pml, is also found in PML nuclear bodies and is the only protein necessary for the formation of PML nuclear bodies (Ishov et al. 1999). In some forms of acute PML, a t(15:17) chromosomal translocation creates a fusion protein of Pml and the retinoic acid receptor (de The et al. 1990, de The et al. 1991; Kakizuka et al. 1991) which influences PML body integrity. Disruption of the PML nuclear bodies, and not the misregulation of the retinoic acid pathway, is the cause of cell transformation (Kogan et al. 2000). Since some components of the PML nuclear body may not function constitutively, or may function at multiple sites throughout the nucleoplasm, it would be predicted that they would be transient occupants of PML nuclear bodies. However, components that are necessary for the integrity of the domains would be predicted to be residents of PML nuclear bodies.

We have shown that nuclei that have not been exposed to extraction or other disruptive procedures possess a protein-based architecture (Hendzel et al. 1999). Surprisingly, such structures completely devoid of chromatin can be enriched in transcription regulatory factors (Hendzel et al. 1998). The core of the PML nuclear body is an example (Boisvert et al. 2000). CAMP response element–binding protein (CBP), a growth suppressor and histone acetyltransferase (Kwok et al. 1994; Arany et al. 1995; Giordano and Avantaggiati 1999), is highly enriched in PML nuclear bodies (LaMorte et al. 1998; Doucas et al. 1999; Boisvert et al. 2000). Whether PML bodies represent aggregations of randomly diffusing proteins, or alternatively are established by an underlying protein-based architecture, remains to be determined. In this study, we show that some components of the PML body are immobile and may play a structural role, whereas at least one other component, CBP, diffuses into and out of the PML body and accumulates in the PML body under some conditions.

	Materials and Methods

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Immunodetection of PML Nuclear Bodies
10T1/2, 293, and SK-N-SH cells were cultured directly on glass coverslips under conditions recommended by the American Type Culture Collection. Cells were fixed with 1.0% paraformaldehyde in PBS (pH 7.5) at room temperature for 5 min. Subsequently, cells were permeabilized in PBS containing 0.5% Triton X-100 for 5 min. PML protein was visualized using an anti-PML antibody (5E10; Stuurman et al.. 1992). CBP was labeled using an anti-CBP NH₂-terminal antibody (no. sc-369, Santa Cruz Biotechnology, Inc.; or no. 06-297, Upstate Biotechnology). Cells were then labeled using the following secondary antibodies: goat anti–rabbit-Cy3 (Chemicon), goat anti–mouse-Cy5 (Amersham Pharmacia Biotech), and goat anti–human-FITC (Jackson ImmunoResearch Laboratories). After rinsing, the samples were mounted in 1 mg/ml paraphenylenediamine in PBS/90% glycerol, containing DNA-specific staining DAPI at 1 µg/ml. Digital deconvolution confocal imaging was performed using a 14-bit cooled CCD camera (Princeton Instruments) mounted on a Leica DMRE immunofluorescence microscope. VayTek Microtome digital deconvolution software was used to remove out-of-focus contributions, and image stacks were projected into one image plane using Scion Image software. False coloring and superimposition was done with Adobe Photoshop^® 5.0.

DNA Constructs and Transient Transfection
The CBP protein (a gift from Dr. X.J. Yang, McGill University, Montreal, Quebec, Canada) has been cloned in the BamHI sites of pEGFP-C1 (CLONTECH Laboratories, Inc.). Sp100 (a gift from Dr. Maul, The Wistar Institute, Philadelphia, PA) was also cloned in pEGFP-C1 (CLONTECH Laboratories, Inc.). The plasmid pCMX–green fluorescent protein (GFP)–PML (a gift from Dr. Evans, The Salk Institute for Biological Studies, La Jolla, CA) has been described elsewhere (Kakizuka et al. 1991). For transient transfection, 2 µg of DNA was diluted in 100 µl of OptiMEM (GIBCO BRL), and 5 µl of Lipofectamine 2000 (GIBCO BRL) was also diluted in 100 µl of OptiMEM. After 5 min at room temperature, the two solutions were mixed and incubated for 20 min to allow complex formation. The mixture was then directly added to the 2 ml of antibiotic-free medium on the cells plated on glass coverslips. The medium was changed 5 h after addition of the transfection mixture, and the cells were allowed to grow for 24 h before fixation.

Interferon Induction
Human 293 cells were grown on coverslips and exposed to human -interferon (Schering) by addition to the medium at a concentration of 1,000 U/ml (Lavau et al. 1995). After 72 h, the cells were fixed and labeled for immunofluorescence microscopy.

Live Cell Imaging
Coverslips were placed on glass slides containing several drops of medium surrounded by vacuum grease. The vacuum grease allows an airtight seal to form. Cells are capable of growing in these conditions for >24 h at 22°C. Individual cells were located by direct viewing through the microscope eyepieces. For FRAP, the laser scanning microscope (LSM 510; ZEISS) was set to laser scanning mode, and the initial imaging conditions were determined. A 25 x 0.8 NA lens was used for these experiments, and pixel sampling was set between 90 and 120 nm per pixel. The argon laser spectral line at a wavelength of 488 nm was set to an intensity of 1.25% of its total power (15 mW) for image collection. A region of interest, such as half of the cell nucleus, was defined, and the software provided with the microscope provided the means to photobleach only this region, using 100 iterations at 25% laser intensity. 12-bit images were collected before, immediately following, and at defined intervals after bleaching. Since significant changes in green fluorescent protein (GFP) signal equilibrium were not observed after 15 min, our total experiment time was set to 900 s to ensure that we observed complete recovery of photobleaching.

	Results

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CBP Presence in PML Nuclear Bodies Depends on the Cell Line
The transcription coactivator CBP is a component of all PML nuclear bodies in HEp-2 (LaMorte et al. 1998), SK-N-SH, COS-1, and CHO cells as detected by immunofluorescence microscopy (Boisvert et al. 2000; Fig. 1A, Fig. F, Fig. K; data not shown). However, we have found that not all cell lines exhibit this property. For example, HeLa, 293, HS-68, and Hep-G2 (Fig. 1 Q; data not shown) cells do not accumulate CBP in PML nuclear bodies. To determine the subnuclear distribution of overexpression of the GFP–CBP fusion protein, 293 cells were transiently transfected with an expression construct coding for this protein. This fusion protein has histone acetyltransferase activity, since the levels of histone H3 and H4 acetylation detected by immunofluorescence rise in proportion to the levels of GFP–CBP overexpression (not shown). This indicates that the GFP tag does not interfere with at least some of CBP's protein–protein interactions. The fusion protein is targeted to PML nuclear bodies as well as being distributed throughout the nucleoplasm (Fig. 1 J). These cells do not normally concentrate CBP in PML nuclear bodies. Furthermore, expression of GFP–Pml (Fig. 1C, Fig. H, Fig. M, and Fig. R) also leads to the accumulation of the endogenous CBP in PML nuclear bodies of these cells (293) (Fig. 1 R). However, overexpression of Sp100 does not bring the endogenous CBP into PML nuclear bodies (Fig. 1D, Fig. I, Fig. N). This shows that the presence of CBP within PML nuclear bodies depends on Pml but not Sp100. Interestingly, expression of Sp100 and Pml increases the number of PML nuclear bodies (Fig. 1H and Fig. I), whereas expression of CBP does not. This indicates that Pml and Sp100, but not CBP, participate in the formation of this nuclear structure.

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Colocalization by deconvolution immunofluorescence microscopy of CBP (NH2 terminus antibody; Santa Cruz Biotechnology, Inc.) and Pml (5E10 antibody) proteins in SK-N-SH cells (A, F, K, and P) but not in 293 cells (B, G, L, and Q). Overexpression of GFP–Pml in 293 cells (C and H) allows proper targeting into PML bodies (C) and concentrates CBP in PML bodies (M and R). Overexpression of GFP–Sp100 in 293 cells (D and I) does not concentrate CBP in PML bodies (N and S). Overexpression of GFP–CBP in 293 cells (E and J) targets this protein to PML bodies (O and T). Bar, 5 µm.

Effect of Interferon on CBP Accumulation in PML Bodies
Overexpression of Pml protein leads to an accumulation of CBP in PML bodies in cells that do not otherwise show this localization. We wished to determine whether induction of Pml by -interferon might also lead to an accumulation of CBP in PML bodies. As expected, after induction of 293 cells with -interferon, the number of PML bodies increased by three- to fourfold and the total immunofluorescence signal increased approximately threefold (not shown), consistent with previous studies (Lavau et al. 1995). After 72 h of exposure to interferon, the CBP distribution changed significantly. Before induction of 293 cells, CBP is distributed in hundreds of small foci throughout the nucleoplasm. There is almost no overlap of these foci with PML bodies. However, after treatment larger foci appear, and many of these colocalize with PML bodies (Fig. 2, objects 1 and 2 in left panel). Other accumulations of CBP, however, are near but do not align precisely with PML bodies (Fig. 2, objects 2 and 3 in right panel). We do not know the basis for the accumulation of CBP into the larger foci that are not PML bodies upon interferon induction, but the accumulation of CBP in PML bodies mimics the accumulation seen when Pml levels are increased through transient overexpression.

View larger version (25K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Localization of Pml and CBP by deconvolution immunofluorescence microscopy after exposure of these 293 cells to -interferon (1,000 U/ml) for 72 h. Bar: (left panel) 5.5 µm; (right, panels 1–3) 1.38 µm.

View larger version (61K): [in this window] [in a new window] [Download PPT slide]   Figure 3 FRAP of half-nucleus of 293 cells expressing GFP–Pml (A), GFP–Sp100 (B), or GFP–CBP (C). Cells were imaged before the bleaching (Pre-Bleached), immediately after the bleaching (Bleached, time = 0 s), and during fluorescence recovery at the indicated times. A box indicates the area bleached, corresponding to half the nucleus. The fluorescence intensity in the bleached and the unbleached regions was measured and expressed as a relative intensity where a value of one is equal intensity in both halves. The relative intensity over time is shown. Fluorescence recovery curves for CBP (D), Pml (E), and Sp100 (F) show the kinetics of redistribution of the different fluorescent proteins after bleaching. As a control, recovery of GFP alone was measured (G).

CBP Moves In and Out of PML Nuclear Bodies
The rate of fluorescence recovery of CBP in PML nuclear bodies is equivalent to that found in the nucleoplasm. To determine whether the direction of CBP movement is only into PML nuclear bodies or is bidirectional into and out of these domains, we performed both FRAP and fluorescence loss in photobleaching (FLIP) experiments. To determine the rate of movement from the nucleoplasm into PML nuclear bodies, we bleached an entire PML nuclear body in a cell expressing GFP–CBP (Fig. 4, A–C). Complete fluorescence recovery of the PML nuclear body was observed after 5 s. This indicates that CBP can move rapidly from the nucleoplasm into PML nuclear bodies. To determine whether CBP can leave the PML nuclear body, we bleached a region just outside the domain to see whether we could drain some fluorescence from it (FLIP) (Fig. 4D and Fig. E). Indeed, we observed a loss of fluorescence from the PML nuclear body followed by a quick reequilibration (5 s) of the fluorescence. The integrated intensity of signal from the PML body shown in Fig. 4 E decreased from 180 to 131 (gray values) after bleaching but rebounded to 160 within 5 s. Our interpretation is that fluorescent molecules that moved from the PML body to the bleached region outside were rapidly replaced (5 s) by fluorescent molecules moving into the PML body from unbleached but nearby regions of the nucleoplasm. Therefore, we conclude that the movement of GFP–CBP between the nucleoplasm and the PML nuclear bodies is bidirectional. The movement cannot be described as freely mobile since it is significantly slower than that seen for a freely diffusing molecule such as GFP (Fig. 3 G). These experiments indicate that CBP in PML nuclear bodies is not an insoluble aggregation of molecules which form by random clustering of diffusing molecules. The bidirectional movement further demonstrates that CBP molecules are not recruited to these domains, stored, and then degraded (Maul 1998).

View larger version (71K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Determination of the direction of movement of GFP–CBP. A whole PML nuclear body was bleached (B, box) in a 293 cell expressing GFP–CBP. 5 s after bleaching, an image showing the fluorescence recovery was recorded (5 s; C). A region just outside the PML nuclear body was then bleached (E, box), indicating that fluorescence can be drained from the PML nuclear body (E), which is followed by a rapid reequilibration (5 s; F) of the fluorescence. Bleached box in Fig. 4 B is 400 nm in length.

Sp100 and PML Are Immobile inside the PML Nuclear Bodies
We wished to determine whether Sp100 and Pml could be distinguished from CBP on the basis of mobility within the PML nuclear body itself. To determine whether GFP-Sp100 is moving within the PML nuclear body, we performed FRAP at high resolution, bleaching a line passing through the middle of a single PML nuclear body (Fig. 5 A). We found that the fluorescence within the PML nuclear body only recovers after relatively long periods (4 min). The same result was obtained for Pml within PML nuclear bodies (data not shown). In contrast, GFP–CBP (Fig. 5 B) fluorescence recovers rapidly from such a treatment, making it difficult to observe the bleached line inside the PML nuclear body in the first image recorded after the bleaching step. After 5 s, the fluorescence of GFP–CBP has been completely redistributed throughout the PML nuclear bodies. The rate of redistribution is greater than that observed when a half nucleus is bleached because the distance the proteins have to travel is comparatively much less. Again, the lack of movement of Sp100 and Pml within the PML nuclear bodies lead us to conclude that they play a structural role in these domains and that the steady-state accumulations of Sp100 and Pml are very stable.

View larger version (54K): [in this window] [in a new window] [Download PPT slide]   Figure 5 FRAP of subregions of PML bodies. A line of photobleaching through the middle of one PML nuclear body (boxes) was created in 293 cells expressing GFP-Sp100 (A) and GFP–CBP (B). After the bleaching, images were recorded over time. Bleached boxes are 300 nm in length.

	Discussion

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We propose that Pml acts as an anchor for concentrating factors such as CBP, thus providing a protein-based rather than DNA-based affinity site able to concentrate CBP in local nuclear volumes. The local accumulation of CBP, a transcriptional coactivator and histone acetyltransferase, may create a domain on the periphery of PML nuclear bodies that is enriched in acetylated and transcriptionally active chromatin. Indeed, we have observed that the chromatin surrounding PML nuclear bodies is highly acetylated, and nascent RNA is associated with the periphery of these domains (Boisvert et al. 2000). We propose that CBP accumulates in regions where a greater concentration is required. Disruption of nuclear bodies, and thereby disruption of the levels of CBP and other PML body components in certain subnuclear volumes, may influence the level of activity of the surrounding genes. Hence, biochemical alteration of the domain, by altering composition or physical integrity, may lead to aberrant gene regulation and a transformed phenotype (Zhong et al. 2000).

	Acknowledgments

 
We thank Ying Ren and Priscilla Hill for technical assistance, and Dr. W. Michael Schoel for assistance with the digital fluorescence microscopy. We are grateful to Dr. R. van Driel for the 5E10 antibody against Pml. F.-M. Boisvert and M.J. Kruhlak were recipients of studentships from the Alberta Heritage Foundation for Medical Research.

The work was funded by an operating grant from the Cancer Research Society, Inc.

Submitted: 14 July 2000

Revised: 17 November 2000

Accepted: 16 January 2001

Abbreviations used in this paper: CBP, CAMP response element–binding protein; GFP, green fluorescent protein; PML, promyelocytic leukemia.

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This Article Abstract Full Text (PDF, 501K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Boisvert, F.-M. Articles by Bazett-Jones, D. P. Search for Related Content PubMed PubMed Citation Articles by Boisvert, F.-M. Articles by Bazett-Jones, D. P. Social Bookmarking                            What's this?