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[Cancer Research 60, 6303-6306, November 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

The Oncogenic Potential of the High Mobility Group Box Protein Sox31

Yu Xia, Nancy Papalopulu, Peter K. Vogt2 and Jian Li

Division of Oncovirology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037 [Y. X., P. K. V., J. L.], and Wellcome/CRC Institute, Cambridge CB2 1QR, United Kingdom [N. P.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Sox proteins belong to the superfamily of high mobility group (HMG) proteins. Sox3 is expressed predominantly in the immature neuroepithelium. Ectopic expression of Sox3 causes oncogenic transformation of chicken embryo fibroblasts (CEFs). The oncogenicity of Sox3 is correlated with nuclear localization and transcriptional regulatory activity; mutants containing deletions in the HMG box or the transactivation domain fail to induce foci of transformation. These observations suggest that Sox proteins can induce aberrant cell growth and strengthen the link of HMG proteins to oncogenesis.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Sox proteins are structurally related to Sry, a testis-determining factor encoded by a gene on the mammalian Y chromosome. They contain a conserved DNA binding motif known as the HMG3 box, which defines one of the HMG superfamilies of nonhistone chromosome proteins (1, 2, 3, 4, 5) . They are divided into seven subgroups, A–G. Members of the same subgroup share ~80% amino acid identity within the HMG box. Sox proteins recognize the heptameric DNA sequence 5'-(A/T)(A/T) CAA (A/T)G-3' as their consensus binding site (6 , 7) . Unlike most transcription factors, these proteins contact DNA in the minor groove and bend DNA 70–85°. They function both as classical transcription factors and as modulators of chromatin structure, possibly regulating access to DNA for other regulatory proteins. Expression patterns and functional analyses suggest that Sox proteins are involved in lens development, chondrogenesis, sex determination, and hemopoiesis. Among the members of the Sox family, Sox3 is most closely related to Sox1, Sox2, and Sox21, all belonging to subgroup B. The human Sox3 gene maps to the region Xq26–27 and is a candidate gene for X-linked mental retardation syndromes including Borjeson-Forssman-Lehmann syndrome and centronuclear myotubular myopathy (8 , 9) . Sox3 is highly expressed in the developing central nervous system. In the developing chicken embryo, transcripts of Sox3 (cSox3) are first detected in the neural plate shortly before neural tube closure. Sox3 expression decreases as development proceeds, correlating with the switch from proliferating to differentiating cells (10) . Sox3 can be phosphorylated by Cdc2 in vitro; whether this phosphorylation regulates Sox3 function is not known (11) . Sox3 was also identified as a potential target of Xenopus brain factor 1, a homologue of the retroviral oncoprotein Qin (12) . In the course of characterizing Qin targets, we evaluated the function of Sox3 in CEFs. The experiments described in this report show that overexpression of Sox3 induces oncogenic transformation of CEFs in culture. The transforming potential of Sox3 requires both the DNA binding domain and the transcriptional regulatory domain of the protein.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Construction of Sox3 Expression Plasmids.
Chicken sox3 cDNA (sequence accession number AB011803, a gift from Dafe Uwanogho, Guy’s Hospital, London, England) was inserted into the retroviral expression vector RCAS (13) and used in stable transfections. The following PCR primers were designed and synthesized for construction of the RCAS-Sox3 plasmids (Fig. 4A)Citation : Sox3-1, 5'-AGC GGG TGC CGG GTC GGA CCA GAC CTT GCT GAA GAA GGA C-3'; Sox3-2, 5'-AGC TCG AAG CTT ATA TGT GAG TTA GTG GTA CAG TGC-3', Sox3-3, 5'-GTA CGC GGA TCC GCC ATG TAT CCT TAC GAT GTA CCA GAC TAT GCG TAC AGC ATG CTG GAG ACC-3'; and Sox3-4, 5'-CTG GTC CGA CCC GGC ACC CG-3'. In the primer Sox3-3, an influenza virus hemagglutinin tag sequence YDYDVPDYA was inserted after the ATG start codon to facilitate immunological detection. pBSFI-Sox3 was generated from a PCR fragment that was obtained with primers Sox3-3 and Sox3-2, digested with BamHI and HindIII, followed by cloning into the pBSFI adapter vector (14) . For the construction of pBSFI-Sox3-{Delta}HMG, two PCR reactions were carried out. One product was amplified with primers Sox3-3 and Sox3-4; the other was generated with Sox3-1 and Sox3-2 primers. These two PCR fragments were cleaved, either with BamHI and BanI or with BanI and HindIII, and then ligated and cloned into the pBSFI vector. pBSFI-Sox3-{Delta}C was obtained by digesting the pBSFI-Sox3 plasmid with PstI, followed by self-ligation. All PCR-amplified fragments were confirmed by sequence analysis. The inserts from the adapter plasmids were subsequently excised by using SfiI endonuclease and cloned into the replication competent avian retrovirus vector RCAS (13) . The RCAS-v-Qin construct has been described (12) .



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  		Fig. 4. Sox3 deletion mutants. A, maps of Sox3 mutant constructs. Arrows, locations of PCR primers used for plasmid construction. B, Western blot analysis of HA-tagged Sox3 proteins. In all constructs, the HA tag (YDYDVPDYA) was inserted between the second and third amino acids of Sox3. C, immunofluorescent staining of cells transfected with RCAS-Sox3 (a), RCAS-Sox3-{Delta}C (b), and RCAS-Sox3-{Delta}HMG (c). x400 . D, focus formation by Sox3 mutants. CEFs were transfected with RCAS-Sox3 constructs at 50 ng of DNA/culture well. The monolayers were stained with 2% crystal violet in 20% methanol 2 weeks after transfection.

 
For tests of transcriptional regulation in transient transfections, chicken sox3 sequences were inserted in-frame into the pGal0 plasmid, which contains the yeast Gal4 DNA binding domain. A PCR product was generated from pBSFI-Sox3 representing full-length Sox3; it was then cleaved with EcoRI and ClaI and cloned into pGal0 to produce pGal0-Sox3; Gal4 constructs of the Sox3 HMG and COOH-terminal domains were likewise generated from PCR products. The reactions were performed with the following primers: HMGs, 5'-TCG AAA GAA TTC GAC CGG GTG AAG CGC CCC ATG-3' and HMGa, 5'-AGC TCG ATC GAT TTA CTT GGT CTT CCT CCG GGG CCG GTA-3'; Cs, 5'-TCG AAA GAA TTC CAG ATG CAC CGC TAC GAC ATG CC-3' and Ca, 5'-AGC TCG ATC GAT TTA CTG CAG GGC CGA AGG GTC TGT GGC-3'. The resultant PCR products were cloned in pGal0 using the same restriction enzymes as described above.

Northern and Western Blot Analyses.
Poly(A)+ RNA was isolated from chicken embryonic brain tissues and from chicken primary fibroblasts with the RNA-STAT-60 kit (TEL-TEST, Inc., Friendswood, TX) and Oligotex mRNA kit (Qiagen, Valencia, CA). RNA was separated by agarose formaldehyde gel electrophoresis, blotted on nylon membranes, and hybridized to the appropriate probes. The following probes were used. The sox3 probe was sequence between nucleotide 1 and nucleotide 1860 of the chicken sox3 cDNA. The qin probe comes from a viral qin cDNA and extends from nucleotide 768 to nucleotide 1397 of that clone. The mouse actin probe (sequence accession number gi191581) was used as a control; it has 88% nucleotide sequence identity with chicken actin. Probes were labeled with [{alpha}-32P]dCTP using a random primer labeling kit (Boehringer-Mannheim, Indianapolis, IN).

Cells transfected with RCAS-Sox3 constructs were harvested after three passages and analyzed by Western blotting. Equal amounts of cellular extracts were separated by SDS-PAGE and transferred onto nitrocellulose membranes (Schleicher & Schuell). The membranes were probed with the monoclonal anti-HA antibody 12CA5 (Covance, Richmond, CA) at a dilution of 1:2000 and a horseradish peroxidase-conjugated sheep antimouse serum at a dilution of 1:3000 (Amersham, Pharmacia Biotech, Piscataway, NJ).

Focus Assay.
CEFs were prepared and transfected according to the protocols described previously (15) . Transfected cells were overlaid with nutrient agar consisting of 2x concentrated F10 medium (42.5%), FCS (3%), chicken serum (1.0%), tryptose phosphate broth (9.0%), DMSO (1.0%), penicillin/streptomycin (1.0%), and a 1.5% solution of sea plaque agar (42.5%) the day after transfection and incubated in a humidified incubator set at 5% CO2 and 37°C until foci of transformed cells developed (10–15 days).

Luciferase Reporter Assay.
CEFs were transfected with 250 ng of a Gal4-Sox3 construct and 100 ng of firefly luciferase reporter plasmid using Lipofectamine according to the manufacturer’s protocol (Life Technologies, Inc., Gaithersburg, MD). Two firefly luciferase reporters CMV-Luc and Gal4-CMV-Luc were used. Gal4-CMV-Luc contains five Gal4 DNA binding sites upstream of the CMV promoter. Transfection efficiency was normalized by cotransfection with 100 ng of the Renilla luciferase plasmid pRL-CMV (Promega Corp., Madison, WI). Transfected cells were harvested at 48 h after transfection. The firefly and Renilla luciferase activities were determined using a luminometer (Wallac Inc., Gaithersburg, MD) and the dual luciferase assay kit (Promega Corp., Madison, WI). Relative luciferase activity is the ratio of firefly to Renilla activities.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
The chicken qin gene codes for a homologue of the mammalian BF-1, and similar to BF-1, the Qin protein is expressed exclusively in the telencephalon (15, 16, 17) . The Qin/BF-1 protein belongs to the forkhead/winged helix family of transcription factors and is required for the development of the cerebral hemispheres (18) . The qin gene has oncogenic potential and occurs as a cell-derived oncogene in an avian sarcoma virus (15) . Injection of in vitro synthesized qin mRNA into the posterior neural plate of Xenopus embryos induces the expression of sox3 (12) . This observation suggests that sox3 plays a role in neuroepithelial cell proliferation and differentiation, possibly as a target gene of the Qin protein. We explored the relationship between qin and sox3 in brain development by analyzing expression in Northern blots. As shown in Fig. 1Citation , both sox3 and qin mRNA are expressed in the developing cerebral hemispheres. Expression of sox3 precedes that of qin. On day 5 of embryonal development, only sox3 mRNA is detectable, and from day 8 to day 20, both messages are present. In contrast to qin, sox3 is also expressed in the midbrain and hindbrain (data not shown). These results show that sox3 can be expressed independently of qin; the two genes have overlapping but not identical expression profiles. In mRNA from RCAS- and RCAS-v-Qin-infected CEFs, sox3 transcripts are barely detectable by Northern blot analysis, further suggesting that qin is not sufficient to drive sox3 expression, and additional tissue-specific regulators are required.



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  		Fig. 1. Expression of Sox3 in chicken embryonic brain tissue and in CEFs. mRNA (1 µg/lane) was prepared from the whole brain of embryos at day 5 (E5; Lane 1), the cerebral hemispheres of embryos at days 8, 10, 12, and 20 (E8, E10, E12, and E20, respectively; Lanes 2–5), and CEFs infected with RCAS and RCAS-v-Qin viruses (RCAS and Qin, respectively; Lanes 6 and 7).

 
The expression of sox3 in proliferating neural epithelium suggests a regulatory role in cell growth. Therefore, we examined the possibility that ectopic expression of sox3 could induce oncogenic transformation. Transfection of RCAS-Sox3 into CEFs led to the appearance of transformed cell foci within 10 days. These foci showed cellular multilayering, but they were smaller and more distinctly demarcated than those induced by RCAS-v-Qin (Fig. 2)Citation . RCAS-Sox3 produced an average of 20–30 foci per 50 ng of DNA. In comparison, RCAS-v-Qin gave rise to 10–15 foci per 50 ng of DNA, and cells transfected with the RCAS vector alone did not develop transformed cell foci. However, unlike Qin, Sox3 failed to stimulate anchorage-independent growth. When RCAS-Sox3 transfected cells were injected s.c. into the wing web of 1-day-old chickens (McIntyre Farms, Lakeside, CA), two of four birds developed small tumors after a latent period of 5–6 weeks, suggesting a marginal tumorigenic potential of the Sox3 protein.



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  		Fig. 2. Sox3-induced transformation of CEF. A, vector control. B, CEFs transfected with RCAS-Sox3. C, CEFs transfected with RCAS-v-Qin. x6.3.

 
Sox3 is a candidate transcriptional regulator, but it is less efficient than other Sox proteins in binding to potential DNA target sequences and in transcriptional activation (5 , 19) . Yet, in its COOH terminal region, Sox3 retains a high degree of homology to the transactivation domain of Sox2 and other members of the Sox protein subgroup B that are potent transcriptional regulators (2) . Because of the difficulties in demonstrating transcriptional activation by native Sox3, it was decided to test specific domains of the protein as Gal4 fusions in transient transfections (Fig. 3A)Citation . The COOH terminal Sox2 homology region of Sox3 functioned as an activator domain in these tests, whereas the Gal4 fusion of the HMG region or the full-length Sox3 protein failed to up-regulate transcription from the Gal4 reporter (Fig. 3B)Citation . These data are compatible with the interpretation that the COOH terminal region of Sox3 contains a transactivation domain that can be masked in the full-length molecule. The nature of this masking is not known.



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  		Fig. 3. A, maps of GAL4-Sox3 constructs. The DNA binding domain (amino acids 1–147) of GAL4 was fused to amino acids 2–316 of Sox3 in GAL0-Sox3, to amino acids 46–124 of Sox3 in GAL0-HMG, and to amino acids 193–289 of Sox 3 in GAL0-C. B, relative luciferase activities in transient transfection assays (n = 3); bars, SE.

 
The role of DNA binding and transcriptional regulation in oncogenic transformation by Sox3 was tested with deletion mutants of the HMG and COOH-terminal domain, respectively. Both mutants were expressed by the RCAS vector in stable transfection of CEFs. Western blot analysis with monoclonal HA antibody confirmed production of the mutant proteins (Fig. 4B)Citation . Immunofluorescent staining located the protein with the COOH terminal deletion as well as full-length Sox3 in the nucleus; these constructs contain the nuclear localization signal of the HMG domain (20) . Deletion of the HMG domain resulted in cytoplasmic localization (Fig. 4C)Citation . In focus assays, RCAS-Sox3-{Delta}HMG failed to transform CEFs, whereas RCAS-Sox3-{Delta}C induced slight multilayering of cells without causing the appearance of distinct foci of transformation (Fig. 4D)Citation . These results suggest that both DNA binding and transcriptional regulation are needed for oncogenic transformation by Sox3. However, the effect of the deletions on oncogenic potential could also reflect conformational changes that are unrelated to the transcriptional regulatory functions of Sox3.

HMG proteins are a diverse group of nonhistone, chromatin-associated proteins of small size and hence high mobility in electrophoresis. They are grouped into three main categories: the HMG-1/HMG-2 and HMG-1 box proteins; the HMG-I(Y) family; and the HMG-14/17 family (4) . These categories differ in structure, mechanism of interaction with DNA, and function. Sox proteins belong to the first category, together with the HMG box transcription factors TCF and LEF (3) .

There is increasing evidence that HMG box proteins as well as members of the HMG(Y) family have oncogenic potential (reviewed in Refs. 21 and 22 ). Expression levels of the HMGI(Y) protein have been correlated with the degree of neoplasia and metastatic tumor progression in cancers of the colon and prostate. Chromosomal translocation of HMGI-C is common in benign mesenchymal tumors. Gain of function in LEF and TCF plays an important role in colon cancer (23) . LEF and TCF combine with ß-catenin to form active transcriptional regulators. ß-Catenin is controlled by a cytoplasmic multiprotein complex that also contains the adenomatous polyposis coli protein, glycogen synthase kinase 3ß, axin, and conductin. Mutations in adenomatous polyposis coli or ß-catenin can increase the stability of ß-catenin, leading to its nuclear translocation and recruitment into transcriptional regulators containing LEF/TCF. The growth-stimulatory action of Sox3 is reminiscent of the role of LEF/TCF in colon cancer. A recent experiment also suggests participation of Xenopus Sox3 in Wnt signaling, showing a physical interaction between Sox3 and ß-catenin (24) . The Sox3 transformation assay in vitro will allow a more detailed genetic analysis of Sox3 domains and their biological functions.


   ACKNOWLEDGMENTS
 
We are grateful to D. Uwanogho, H. Xu, C. Sonderegger, and F. J. Rauscher, III, for providing chicken Sox3, actin cDNA, Gal4-CMV-Luc, and pGal0 plasmids.


   FOOTNOTES
 
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.

1 Supported by USPHS Grants CA42564 and CA79616 (to P. K. V.), Grant 4053 from the Council for Tobacco Research USA, Incorporated (to J. L.), and Grant RPG-97-069-01-VM from the American Cancer Society (to J. L.). Y. X. is a recipient of a NIH training fellowship. This is manuscript number 12687-MEM at The Scripps Research Institute. Back

2 To whom requests for reprints should be addressed, at Division of Oncovirology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC239, La Jolla, CA 92037. Phone: (858) 784-9728; Fax: (858) 784-2070; E-mail: pkvogt{at}scripps.edu Back

3 The abbreviations used are: HMG, high mobility group; CEF, chicken embryo fibroblast; CMV, cytomegalovirus; BF, brain factor; TCF, T-cell factor; LEF, lymphoid enhancer factor. Back

Received 4/12/00. Accepted 10/ 3/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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