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J. Biol. Chem., Vol. 279, Issue 12, 10829-10832, March 19, 2004

This Article Abstract Full Text (PDF) Supplemental Data All Versions of this Article: 279/12/10829    most recent C400035200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaplan, D. D. Articles by Casey, P. J. Search for Related Content PubMed PubMed Citation Articles by Kaplan, D. D. Articles by Casey, P. J.

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Identification of a Role for -Catenin in the Establishment of a Bipolar Mitotic Spindle^*

Daniel D. Kaplan, Thomas E. Meigs¶, Patrick Kelly||, and Patrick J. Casey**

From the Departments of Pharmacology and Cancer Biology and ^**Biochemistry, Duke University Medical Center, Durham, North Carolina 27710

Received for publication, January 20, 2004

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
-Catenin is a multifunctional protein that is known to participate in two well defined cellular processes, cell-cell adhesion and Wnt-stimulated transcriptional activation. Here we report that -catenin participates in a third cellular process, the establishment of a bipolar mitotic spindle. During mitosis, -catenin relocalizes to mitotic spindle poles and to the midbody. Furthermore, biochemical fractionation demonstrates the presence of -catenin in purified centrosome preparations. Reduction of cellular -catenin by RNA interference leads to the failure of centrosomes to fully separate, resulting in a marked increase in the frequency of monoastral mitotic spindles. Our results define a new and important function for -catenin in mitosis and demonstrate that -catenin is involved in vital biological processes beyond cell adhesion and Wnt signaling.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
The faithful distribution of the genetic material between daughter cells during cell division requires the precise segregation of duplicated chromosomes. This crucial duty is performed by a microtubule-based machine known as the mitotic spindle (1). The dynamic interactions of numerous structural and motor proteins underlie the formation of a bipolar mitotic spindle (1, 2). However, many of the molecules that regulate spindle assembly remain elusive (3).

-Catenin is a multifunctional protein with critical roles in both cell-cell adhesion and transcriptional regulation (4, 5). In cooperation with -catenin, -catenin links cadherins to the actin cytoskeleton, thereby establishing a junctional complex that is required for strong cell-cell adhesion (4, 6, 7). -Catenin also functions in signal transduction as a component of the Wnt/Wingless pathway that is crucial for development (5, 8, 9). The Wnt signal frees -catenin from a cytoplasmic complex that normally targets it for degradation, thereby allowing the protein to accumulate and translocate to the nucleus (10) where it complexes with transcription factors of the T cell factor (TCF)¹/lymphoid enhancer factor family (11, 12) to stimulate the expression of genes involved in cell growth and proliferation (5, 10). Defects in the control of Wnt/-catenin signaling that result in aberrant accumulation of -catenin are observed in many cancers (13). Here we present evidence that -catenin has a cellular role in addition to cell adhesion and Wnt signaling. We demonstrate that -catenin is a component of the mammalian mitotic spindle and that it functions to ensure proper centrosome separation and the subsequent establishment of a bipolar spindle.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Materials—The cDNAs for Xenopus -catenin-myc and -catenin-GFP (green fluorescent protein) were a gift from Randall Moon (University of Washington) and that for Myc-N-TCF was a gift from Bert Vogelstein (Johns Hopkins University). Anti--catenin mouse monoclonal antibodies were from Zymed Laboratories Inc. and BD Transduction Laboratories; anti--tubulin-Cy3 directly conjugated mouse monoclonal antibody and anti--tubulin mouse monoclonal antibody were from Sigma; anti--tubulin rabbit polyclonal antibody was from Berkeley Antibody Co.; anti-actin goat polyclonal antibody was from Santa Cruz Biotechnology; and anti-c-myc mouse monoclonal antibody was from Zymed Laboratories Inc.

Cell Culture and Transfection—L and HEK 293 cells were grown in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum; NIH 3T3 cells were grown in Dulbecco's modified Eagle's medium containing 10% calf serum; and HeLa cells were grown in MEM containing 10% fetal bovine serum, 0.1 mM non-essential amino acids, and 1.0 mM sodium pyruvate. For Fig. S1C, L or NIH 3T3 cells were transfected using LipofectAMINE (Invitrogen) with an expression vector encoding Xenopus -catenin fused to GFP (14).

Generation of Stable HeLa Cell Lines—Xenopus -catenin with six myc epitopes appended to the C terminus was subcloned into the retroviral vector pLPCX (BD Biosciences). Control or Xenopus -catenin retrovirus was produced by transfecting a HEK 293 virus-packaging cell line with empty pLPCX vector or pLPCX encoding Xenopus -catenin, respectively. Recombinant retroviruses were harvested from the media of the transfected HEK 293 cells and used to infect HeLa cells. HeLa cells expressing the viruses were selected and maintained in normal HeLa media additionally containing puromycin (2 µg/ml).

Production of Wnt-3A-conditioned Media—Media were harvested from confluent L cells expressing Wnt-3A or a control vector (courtesy of Karl Willert, Stanford University), cleared by centrifugation, and filtered.

Immunofluorescence and Microscopy—Cells shown in Figs. 1 and 3C were grown on coverslips and fixed rapidly according to established protocols (15, 16) in 4% paraformaldehyde, pH 11, for 10 min at room temperature. The same staining pattern was observed with an alternate protocol (17) involving permeabilization in 0.5% Triton X-100 and fixation at pH 7 (Figs. 3D and S1, A and B). Antibody incubations were as follows: Figs. 1, 3C, and S1, A and B, Zymed Laboratories Inc. anti--catenin (1:100), fluorescein isothiocyanate-conjugated anti-mouse (1:100), and Cy3-conjugated anti--tubulin (1:100); Fig. 3D, Sigma anti--tubulin (1:1000), fluorescein isothiocyanate-conjugated anti-mouse (1:100), and Cy3-conjugated anti--tubulin (1:100). In all cases, DNA was stained using Hoechst 33342 (1:1000) in phosphate-buffered saline. For Fig. 3D, centrosome number was assessed by -tubulin staining as described previously (18). Images were obtained using an LSM-410 laser scanning confocal microscope with a 40x or 63x oil immersion objective (Carl Zeiss). All images are single confocal sections with the exception of those in Fig. S1C, which were taken using a Nikon TE300 fluorescence light microscope.

View larger version (27K): [in this window] [in a new window]   FIG. 1. -Catenin localization in mitotic cells. L cells were fixed, and the localization of -catenin (green in merge), -tubulin (red in merge), and DNA (blue in merge) were examined. -Catenin localizes to spindle poles in metaphase (A) and anaphase (B) cells. Early in telophase (C), -catenin is observed both at spindle poles and the forming midbody, whereas late in telophase (D) it is concentrated at the midbody.

View larger version (32K): [in this window] [in a new window]   FIG. 3. Reduction of -catenin increases the incidence of monoastral spindles. A, immunoblot analysis of lysates from HeLa cells treated with siRNA directed against -catenin or a control sequence. B and C, HeLa cells were fixed 64 h after siRNA transfection, and the localization of -catenin (green in merge), -tubulin (red in merge), and DNA (blue in merge) were examined. Mitotic spindles were visualized by -tubulin staining. For each condition, the fraction of mitotic cells exhibiting monoastral spindles is shown in B. In C, an example of a monoastral spindle in a -catenin siRNA-treated cell (top) and a normal, bipolar spindle in a control-treated cell (bottom) are shown. Note that the only -catenin staining remaining in the -catenin siRNA-treated cell is seen at the hub of the monoastral spindle. D, monoastral spindles caused by reduction of -catenin result from unseparated centrosomes. Shown is a mitotic HeLa cell treated with -catenin siRNA, fixed, and stained for -tubulin (red in merge), centrosomes (anti--tubulin, green in merge), and DNA (blue in merge).

RNA Interference—Double-stranded 21-mer RNA oligonucleotides homologous to sequences in human -catenin (20) and the luciferase plasmid pGL2 (21) were purchased as desalted, deprotected, purified duplexes (Dharmacon Research). HeLa cells were transfected with the RNA duplexes using Oligofectamine as described previously (20) and harvested 64 h post-transfection for analysis.

Immunoblotting—Equal amounts of each fraction (for analysis of sucrose fractions from the centrosome preparation) or equal amounts of protein from each small interfering RNA (siRNA)-transfected cell lysate (for analysis of siRNA-mediated reduction of protein levels) were heated in SDS sample buffer, separated by SDS-PAGE, and transferred to nitrocellulose membranes. Immunoblot analyses were performed using anti--catenin (BD Transduction Laboratories), anti--tubulin (Berkeley Antibody Co.), anti-plakoglobin (Zymed Laboratories Inc.), and anti-actin, followed by the addition of horseradish peroxidase-conjugated secondary antibodies and subsequent chemiluminescence detection.

Analysis of Spindle Morphology—HeLa cells were fixed 64 h after transfection with siRNA, and immunofluorescence staining was performed as described above. Mitotic cells were scored as having normal bipolar spindles or monoastral spindles, and the percentage of mitotic cells with monoastral spindles were represented as [(No. of monoastral spindles/total no. of mitotic cells) x 100]. Data represent the mean ± S.E. of the mean of three independent experiments in which >2000 cells were analyzed per experiment.

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
We were prompted to investigate the possibility that -catenin has an important cellular role in addition to cell adhesion and Wnt signaling while examining the fate of -catenin released from the cadherin cytoplasmic domain (22, 23). In the process of these studies, we noticed an unusual staining pattern of -catenin in mitotic cells and decided to examine its distribution more carefully during the cell cycle. During interphase, endogenous -catenin was seen to localize diffusely throughout the cytoplasm and nucleus and at cell-cell junctions (Fig. S1A). However, during M phase, -catenin localized strikingly to the centrosomal region at the poles of the mitotic spindle and to the spindle midzone during midbody formation (Fig. 1). This staining pattern was observed in mitotic L, NIH 3T3, PtK1, and HeLa cells. -Catenin first became concentrated at centrosomes during metaphase (Fig. 1A) and remained at the spindle poles during anaphase and early telophase (Fig. 1, B and C). As the cleavage furrow constricted between the two daughter cells, -catenin also appeared at the midbody (Fig. 1C). By late telophase, -catenin was no longer seen at the centrosomes, but it remained concentrated at the midbody (Fig. 1D). This staining pattern was not observed when the primary antibody was pre-incubated with purified -catenin, nor was it observed when the primary antibody or secondary antibody was omitted, nor when a control IgG primary antibody was used (data not shown). Furthermore, when a fusion of -catenin to GFP (14) was expressed in L cells and NIH 3T3 cells, the protein localized to the spindle poles and the midbody in live, mitotic cells (Fig. S1C), just as was observed for endogenous -catenin in fixed cells. Additionally, we were unable to detect any concentration of the -catenin homolog plakoglobin at mitotic spindle poles or the midbody, indicating that the observed localization is specific for -catenin (data not shown). This dramatic redistribution of -catenin during mitosis is suggestive of a function for this protein distinct from its interphase roles.

As an independent approach to confirm the association of -catenin with centrosomes, we isolated centrosomes from L cells and HeLa cells using an established method (19). Immunoblot analysis of fractions from the final step in the purification procedure revealed that -catenin was indeed present in this centrosomal preparation, where it co-fractionated with -tubulin (Fig. 2, top panel), a core component of the centrosome (24). The two proteins were concentrated at the position of the sucrose gradient corresponding to a sucrose concentration of 49–57% (Fig. 2, bottom panel), the position where centrosomes have been reported to sediment (19).

View larger version (52K): [in this window] [in a new window]   FIG. 2. -Catenin and -tubulin co-fractionate in a centrosomal preparation. Centrosomes were isolated according to the method of Mitchison and Kirschner (19), in which the final purification step was a continuous sucrose gradient. Fractions were collected and assayed for protein content and for sucrose concentration (bottom panel). Because centrosomal material is reported to sediment between 50 and 58% sucrose in this procedure (19), fractions between 48 and 60% sucrose were subjected to immunoblot analysis for the centrosomal marker -tubulin (24) and for -catenin; as a control, fractions were also analyzed for actin (top panel).

Monoastral spindles can result from defects in centrosome duplication or from defects in centrosome separation (26). To begin to explore the mechanism through which depletion of -catenin disrupts bipolar spindle formation, we assessed the number of centrosomes in the monoastral spindles of -catenin-depleted cells. All of the monoastral spindles examined exhibited two puncta of -tubulin staining (Fig. 3D, arrowheads), indicating that the centrosomes had duplicated but were not properly separated.

To verify that the observed increase in monoastral mitotic spindles was specifically due to loss of -catenin, we performed a rescue experiment by reintroducing a form of -catenin that would be refractory to siRNA. We accomplished this using Xenopus -catenin, the amino acid sequence of which is 95% identical to human -catenin but which has two nucleotides in the siRNA target sequence that differ from those in human -catenin. Because even a single mismatch in the target sequence has been shown to abolish siRNA-mediated gene silencing (27), we reasoned that Xenopus -catenin should be highly refractory to siRNA directed against human -catenin. We generated stable HeLa cell lines expressing either myc-tagged Xenopus -catenin or a control vector (Fig. 4A) and then used siRNA to knock down the endogenous -catenin without disrupting the ectopically expressed Xenopus -catenin (Fig. 4A). Examination of the spindle morphology of these cells revealed that treatment with -catenin siRNA resulted in a clear increase in monoastral mitotic spindles in those cells expressing the control retrovirus but no increase in those cells expressing the Xenopus -catenin retrovirus (Fig. 4B). These data indicate that introduction of Xenopus -catenin can rescue the mitotic defect caused by -catenin siRNA treatment and provide verification that the observed increase in monoastral mitotic spindles is due specifically to the loss of -catenin. The specificity of this phenotype is further demonstrated by our observations that reduction of plakoglobin levels using siRNA does not result in an increase in monoastral mitotic spindles and that plakoglobin overexpression cannot effectively rescue the monoastral spindle phenotype caused by reduction of cellular -catenin.²

View larger version (34K): [in this window] [in a new window]   FIG. 4. Ectopic expression of Xenopus -catenin rescues the mitotic defect caused by -catenin siRNA treatment. Stable HeLa cell lines were generated by infection with control retrovirus or retrovirus encoding myc-tagged Xenopus -catenin, and these cell lines were subsequently treated with siRNA directed against -catenin or a control sequence. In A, immunoblot analysis of lysates from these cells is shown. The Xenopus -catenin has six myc epitopes appended to its C terminus and therefore migrates at a higher molecular weight than the endogenous -catenin. For each condition, the fraction of mitotic cells exhibiting monoastral spindles is shown in B.

The identification herein of a novel function for -catenin in centrosome separation suggests that -catenin plays a more general role as a molecular scaffold than previously thought. This notion is supported by some interesting observations that have come from genetic studies in Drosophila and Caenorhabditis elegans suggesting a possible role for homologs of -catenin in orienting or anchoring the mitotic spindle (28, 29), as well as by the finding that -catenin may anchor microtubules at adherens junctions via its interaction with dynein (30). In both cell adhesion and Wnt signaling, -catenin acts as an adaptor to direct the local formation of functional protein complexes (31). It seems likely that -catenin is employed in a similar capacity in mitotic spindle formation. A complex assemblage of many structural and motor proteins is required to establish a bipolar mitotic spindle (1, 2). -Catenin may regulate this dynamic process to ensure that components of the mitotic machinery are assembled in the correct place and at the correct time for cell division to proceed efficiently. Clearly, the identification of the binding partners of -catenin at the centrosomes and midbody will be essential to a complete mechanistic understanding of its role in mitosis.

	FOOTNOTES

 
^* This work was supported by National Institutes of Health Grants CA91159 and CA100869 [GenBank] . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

Howard Hughes Medical Institute Predoctoral Fellow.

^¶ Present address: Dept. of Biology, University of North Carolina at Asheville, Asheville, NC 28804.

^|| Duke University Medical School Alumni M.D./Ph.D. Scholar.

To whom correspondence should be addressed. Tel.: 919-613-8613; Fax: 919-613-8642; E-mail: casey006{at}mc.duke.edu.

¹ The abbreviations used are: TCF, T cell factor; GFP, green fluorescent protein; siRNA, small interfering RNA.

² D. D. Kaplan, A. Kowalczyk, and P. J. Casey, unpublished observations.

	ACKNOWLEDGMENTS

 
We thank K. Swenson-Fields for valuable input throughout the course of this project, A. Bejsovec, S. Kornbluth, D. Lew, R. B. Nicklas, and T.-P. Yao for constructive discussions and critical reading of the manuscript, M. Bienz and R. Rosin-Arbesfeld for providing information regarding the siRNA sequence and protocol used for targeting -catenin, R. Moon, B. Vogelstein, and K. Willert for providing reagents, and F. A. Chow, C. Hubbert, A. Seeds, J. Shearer, and members of the Casey laboratory for helpful suggestions.

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TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 

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This Article Abstract Full Text (PDF) Supplemental Data All Versions of this Article: 279/12/10829    most recent C400035200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaplan, D. D. Articles by Casey, P. J. Search for Related Content PubMed PubMed Citation Articles by Kaplan, D. D. Articles by Casey, P. J.