Carcinogenesis

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (36) Request Permissions Google Scholar Articles by Moennikes, O. Articles by Schwarz2, M. Search for Related Content PubMed PubMed Citation Articles by Moennikes, O. Articles by Schwarz2, M. Social Bookmarking          What's this?

Carcinogenesis, Vol. 20, No. 7, 1379-1382, July 1999
© 1999 Oxford University Press

Short Communications

The effect of connexin32 null mutation on hepatocarcinogenesis in different mouse strains

Oliver Moennikes, Albrecht Buchmann, Thomas Ott¹, Klaus Willecke1¹ and Michael Schwarz2²

Institut für Toxikologie, Wilhelmstraße 56, 72074 Tübingen and
¹ Institut für Genetik, Bonn, Germany

This paper is dedicated to Prof. H.Remmer on the occasion of his 80th birthday

	Abstract

Top Abstract Introduction References

 
Connexin32 (Cx32) is the major gap junctional protein in mouse liver. We have shown recently that the formation of liver tumours in Cx32-deficient mice is strongly increased in comparison with control wild-type mice, demonstrating that the deficiency in gap junctional communication has an enhancing effect on hepatocarcinogenesis. We have now compared the effect of Cx32 deficiency on liver carcinogenesis in two strains of mice with differing susceptibility to hepatocarcinogenesis. Heterozygous Cx32^+/– females were crossed with male Cx32 wild-type C57BL/6J (low susceptibility) or C3H/He (high susceptibility) mice. Since the Cx32 gene is located on the X-chromosome, the resulting F1 males segregated to the genotypes Cx32^Y/+ and Cx32^Y/–. Genotyping was performed by PCR-analysis using tail-tip DNA. Weanling male mice were i.p. injected with a single dose of N-nitrosodiethylamine and were killed 16, 21 or 26 weeks later. The number, volume fraction and size distribution of precancerous liver lesions characterized by a deficiency in the marker enzyme glucose-6-phosphatase were quantitated. The results demonstrate that Cx32 deficiency only slightly affects the number of enzyme-altered lesions, but strongly enhances their growth, both in the resistant and the susceptible mouse strain, suggesting that decreased intercellular communication results in tumour promoting activity irrespective of the genetic background of the mouse strain used. Since Cx32-deficient C3H/He hybrids were ~5–10 times more sensitive than C3H/He hybrids with an intact Cx32 gene, this mouse strain may prove very useful for toxicological screening purposes.

Abbreviations: Cx32, connexin32; G-6-Pase, glucose-6-phosphatase; DEN, N-nitrosodiethylamine.

	Introduction

Top Abstract Introduction References

 
Connexins are subunits of gap junction channels, through which low molecular molecules such as ions, second messengers and metabolites can be exchanged between neighbouring cells. Intercellular communication mediated via gap junctions has been suggested to play a role in tissue homeostasis, embryonic development and cancer (for recent reviews see 1,2). The important role of gap junctional communication in multi-stage carcinogenesis is demonstrated by several lines of evidence: (i) gap junctions are often found to be decreased in tumour tissue (3–5); (ii) overexpression of connexins suppresses tumorigenicity of tumour-forming cells (6); and (iii) the introduction of activated oncogenes into cells blocks intercellular communication (7,8), an effect that is also characteristic of tumour-promoting agents such as 12-O-tetradecanoylphorbol-13-acetate (for reviews see 9–11). Moreover, we have shown recently that targeted disruption of the connexin32 (Cx32) gene in mice is associated with a high incidence of spontaneous and chemically induced liver tumours, directly demonstrating the tumour-suppressive role of this connexin in mouse liver (12).

It is well documented that different strains of mice show characteristic differences in susceptibility to hepatocarcinogenesis (for reviews see 13,14). C3H/He mice, for example, show a high rate of spontaneously occurring liver tumours and are highly susceptible to chemically induced hepatocarcinogenesis. On the contrary, the background incidence of liver tumours in C57BL/6J mice is low and mice of this strain are comparatively resistant to hepatocarcinogenesis (15). Genetic loci that confer susceptibility as well as loci that suppress hepatocarcinogenesis have been identified by linkage analysis (13–18). The nature of the underlying genes, however, remains obscure. The present study was aimed to investigate the possible relationship between genetic background and Cx32 deficiency regarding hepatocarcinogenesis.

The Cx32-deficient mouse mutant used in the present study was orginally generated by standard methods of targeted homologous recombination leading to a mixed genetic background of C57BL/6J and 129Sv inbred strains (19). Female Cx32^+/– heterozygous mice were bred with male C57BL/6J or C3H/He mice, which harbour a normal Cx32 allele (Cx32^Y/+). C3H/He and C57BL/6J strains and the resulting F1 generations will be abbreviated as C3H, C57BL, C3H-F1 and C57BL-F1, respectively, from here on. Males of the F1-generations should theoretically split into Cx32^Y/– and Cx32^Y/+ at a 1:1 ratio. We found a slight, but not significant, under-representation of Cx32^Y/– mice (30 Cx32^Y/– versus 43 Cx32^Y/+), which led to slightly smaller numbers of Cx32-deficient mice in the respective groups. Twelve to 15 days after birth, all mice were given a single i.p. injection of 10 mg/kg body weight of N-nitrosodiethylamine (DEN). Tail-tips were taken and Cx32-genotyping was performed by standard PCR using primers I, 5'-CCATAAGTCAGGTGTAAAGGAGC-3', and II, 5'-AGATAAGCTGCAGGGACCATAGG-3', for amplification of the Cx32 wild-type allele, and primers I and III, 5'-ATCATGCGAAACGATCCTCATCC-3', for amplification of the Cx32-defective allele. The resulting DNA fragments were 550 and 414 bp in length, respectively. PCR products were separated by PAGE and stained with ethidium bromide. A representative example is shown in Figure 1. Groups of mice were killed at 16, 21 and 26 weeks after carcinogen treatment. Livers were removed and frozen on blocks of dry ice. Frozen sections were taken from three lobes of each liver and stained enzyme-histochemically for glucose-6-phosphatase (G-6-Pase) activity (20). G-6-Pase-negative lesions were quantitated by means of a computer-assisted digitizer system (21). Number and volume fraction in liver as well as size distribution of lesions were calculated using standard stereological techniques (22).

View larger version (54K): [in this window] [in a new window]   Fig. 1. Cx32 genotyping by PCR. DNA was extracted from tail-tips and subjected to PCR using primer pairs specific for Cx32 wild-type (Cx32+) or Cx32 null (Cx32–) alleles. PCR products were separated by SDS–PAGE and stained with ethidium bromide. Cx32– specific PCR products were obtained with DNA samples from mice nos 1–3 and 8 (Cx32Y/– genotype), while mice nos 4–7 and 9 showed Cx32+ specific PCR products (Cx32Y/+ genotype). M, marker lane; n, negative control (PCR reaction without DNA).

 
The results of the quantitative analysis are summarized in Figure 2. There were only minor changes in the number of enzyme-altered lesions with time after treatment. This was not unexpected when using a treatment regimen with single carcinogen administration. The numbers of lesions in Cx32-deficient C57BL-F1 mice, however, were significantly higher than in the respective wild-type controls (P < 0.0001), while this effect was statistically borderline in C3H-F1 mice (P = 0.0504). The volume fraction occupied in liver by G-6-Pase-deficient tissue increased strongly as a function of time after DEN treatment in all treatment groups (P < 0.0001), indicating the time-dependent growth of enzyme-deficient liver lesions. As expected, the volume fractions of enzyme-altered tissue were, at all three time points, significantly smaller in C57BL-F1 mice than in C3H-F1 mice. The Cx32-defect caused a dramatic enhancing effect on growth of liver lesions in both strains of mice (~5-fold in C3H-F1; P < 0.0001, and ~7-fold in C57BL-F1 mice; P < 0.0001). Interestingly, the volume fractions of lesions in Cx32^Y/– mice of the C57BL-derived F1-generation were always higher than those in Cx32^Y/+ mice of the C3H-derived F1-strain, indicating that the Cx32 gene defect enhances hepatocarcinogenesis more efficiently than the susceptibility gene(s) inherited from C3H mice. The enhancing effect of Cx32-deficiency on growth of enzyme-deficient lesions is also clearly demonstrated by the size class distribution of liver lesions (Figure 3). In both F1 strains, lesions in livers of Cx32^Y/– mice were shifted towards the larger diameter classes and the largest diameter classes were always occupied by lesions from the gene knockout animals.

View larger version (21K): [in this window] [in a new window]   Fig. 2. Quantitative analysis of G-6-Pase-deficient liver lesions. Weanling Cx32Y/+ and Cx32Y/– F1 mice with C3H and C57BL genetic backgrounds were given a single injection of DEN and were killed at the indicated time points thereafter. Frozen liver sections were histochemically stained for G-6-Pase activity, and G-6-Pase-deficient liver lesions were quantitated by use of a computer assisted digitizer system. The number of lesions per cm3 liver and their volume fraction in liver were calculated subsequently by stereological methods. Values are means plus standard deviations. Numbers of animals in the various groups are indicated. Statistical analysis was performed with two-way ANOVA with interaction terms for time and genotype using PROC GLM in the analysis software SAS v.6.12 (SAS, Casy, NC). Data on statistical analysis are given in the text.

 

View larger version (32K): [in this window] [in a new window]   Fig. 3. Effect of Cx32 deficiency on size distribution of G-6-Pase-negative liver lesions in mice of the indicated genetic backgrounds. The size distributions of lesions observed 16–26 weeks after DEN treatment were calculated by stereological procedures from the 2-dimensional observations. The upper limits of the diameter classes increase logarithmically from class 1, antilog 2.0 (100 µm), class 2, antilog 2.1 (126 µm), class 3, antilog 2.2 (158 µm), . . . class 17, antilog 3.6 (3981 µm). Note that the largest diameter classes are always occupied by lesions from Cx32Y/– mice. Although the numbers of lesions within these size classes are only small, they contribute mostly to the volume fraction occupied by enzyme-altered tissue in liver.

 
In accordance with our previous data (12), the results of the present study demonstrate that Cx32 deficiency strongly enhances the growth of enzyme-altered lesions in mouse liver. This confirms the importance of gap junctional communication in suppression of tumorigenesis, although the molecules that are exchanged between cells and suppress tumour cell proliferation remain to be discovered. The accelerating effect of Cx32 deficiency on liver carcinogenesis was seen in F1 hybrids of both C3H and C57BL mice, which are characterized by a high and low susceptibility to hepatocacinogenesis, respectively. The genetic basis for interstrain differences in susceptibility to carcinogenesis has been intensively investigated, and various gene loci that confer susceptibility or resistance to hepatocarcinogenesis have been mapped to different chromosomal locations (13–18). Liver lesions can be induced at similar rates in livers of susceptible C3H and resistant C57BL mice but differ with respect to their growth properties (14,16), an observation that has also been made in the present investigation (Figure 2). The increased velocity of tumour growth in livers of C3H mice is paralleled by higher rates of DNA synthesis in normal liver tissue when compared with the more resistant C57BL strain (23). An increase in the frequency of DNA synthesizing hepatocytes is also characteristic of Cx32-deficient mice (12), suggesting that enhanced turnover of hepatocytes in the normal liver tissue may be linked to enhanced proliferation of their neoplastically transformed counterparts. The functional Cx32 gene product may therefore mediate suppression of proliferation of hepatocytes both in normal and neoplastically transformed liver tissue.

All known modifier genes in the mouse that confer susceptibility or resistance to hepatocellular cancer have been mapped to autosomal locations (for a recent review, see 18). In contrast, the Cx32 gene is located on the X-chromosome and is thus different from the other cancer resistance genes identified by genetic linkage analysis performed on mouse strains with low and high liver cancer susceptibility. The Cx32 gene product is a powerful tumour suppressor, which, when functionally deleted, strongly affects hepatocarcinogenesis in mice. Since this gene defect leads to a further enhancement of liver cancer development in mice with high predisposition to hepatocarcinogenesis (data herein), Cx32-null C3H mice may prove very useful for toxicological screening purposes.

	Acknowledgments

 
We thank Mrs Elke Zabinski for excellent technical assistence, and Dr Annette Kopp-Schneider for help in statistical analysis.

	Notes

 
² To whom correspondence should be addressed Email: michael.schwarz{at}uni-tuebingen.de

	References

Top Abstract Introduction References

 

1. Kumar,N.M. and Gilula,N.B. (1996) The gap junction communication channel. Cell, 84, 381–388.[Web of Science][Medline]
2. Yamasaki,H. and Naus,C.C. (1996) Role of connexin genes in growth control. Carcinogenesis, 17, 1199–1213.[Free Full Text]
3. Janssen Timmen,U., Traub,O., Dermietzel,R., Rabes,H.M. and Willecke,K. (1986) Reduced number of gap junctions in rat hepatocarcinomas detected by monoclonal antibody. Carcinogenesis, 7, 1475–1482.[Abstract/Free Full Text]
4. Krutovskikh,V.A., Oyamada,M. and Yamasaki,H. (1991) Sequential changes of gap-junctional intercellular communications during multistage rat liver carcinogenesis: direct measurement of communication in vivo. Carcinogenesis, 12, 1701–1706.[Abstract/Free Full Text]
5. Neveu,M.J., Hully,J.R., Babcock,K.L., Hertzberg,E.L., Nicholson,B.J., Paul,D.L. and Pitot,H.C. (1994) Multiple mechanisms are responsible for altered expression of gap junction genes during oncogenesis in rat liver. J. Cell Sci., 107, 83–95.[Abstract]
6. Rose,B., Mehta,P.P. and Loewenstein,W.R. (1993) Gap-junction protein gene suppresses tumorigenicity. Carcinogenesis, 14, 1073–1075.[Abstract/Free Full Text]
7. Hayashi,T., Nomata,K., Chang,C.C., Ruch,R.J. and Trosko,J.E. (1998) Cooperative effects of v-myc and c-Ha-ras oncogenes on gap junctional intercellular communication and tumorigenicity in rat liver epithelial cells. Cancer Lett., 128, 145–154.[Web of Science][Medline]
8. Jou,Y.S., Layhe,B., Matesic,D.F., Chang,C.C., De Feijter,A.W., Lockwood,L., Welsch,C.W., Klaunig,J.E. and Trosko,J.E. (1995) Inhibition of gap junctional intercellular communication and malignant transformation of rat liver epithelial cells by neu oncogene. Carcinogenesis, 16, 311–317.[Abstract/Free Full Text]
9. Trosko,J.E. and Chang,C.C. (1988) Chemical and Oncogene Modulation of Gap Junctional Intercellular Communication. Raven Press, New York, NY.
10. Swierenga,S.H. and Yamasaki,H. (1992) Performance of Tests for Cell Transformation and Gap-junctional Intercellular Communication for Detecting Nongenotoxic Carcinogenic Activity. IARC Scientific Publications No. 116, IARC, Lyon, pp. 165–193.
11. Budunova,I.V. and Williams,G.M. (1994) Cell culture assays for chemicals with tumor-promoting or tumor-inhibiting activity based on the modulation of intercellular communication. Cell Biol. Toxicol., 10, 71–116.[Web of Science][Medline]
12. Temme,A., Buchmann,A., Gabriel,H.D., Nelles,E., Schwarz,M. and Willecke,K. (1997) High incidence of spontaneous and chemically induced liver tumors in mice deficient for connexin32. Curr. Biol., 7, 713–716.[Web of Science][Medline]
13. Drinkwater,N.R. and Bennett,L.M. (1991) Genetic control of carcinogenesis in experimental animals. Prog. Exp. Tumor Res., 33, 1–20.[Web of Science][Medline]
14. Drinkwater,N.R. (1994) Genetic control of hepatocarcinogenesis in C3H mice. Drug Metab. Rev., 26, 201–208.[Web of Science][Medline]
15. Drinkwater,N.R. and Ginsler,J.J. (1986) Genetic control of hepatocarcinogenesis in C57BL/6J and C3H/HeJ inbred mice. Carcinogenesis, 7, 1701–1707.[Abstract/Free Full Text]
16. Dragani,T.A., Manenti,G., Gariboldi,M., De Gregorio,L. and Pierotti,M.A. (1995) Genetics of liver tumor susceptibility in mice. Toxicol. Lett., 82/83, 613–619.
17. Manenti,G., Binelli,G., Gariboldi,M., Canzian,F., De Gregorio,L., Falvella,F.S., Dragani,T.A. and Pierotti,M.A. (1994) Multiple loci affect genetic predisposition to hepatocarcinogenesis in mice. Genomics, 23, 118–124.[Web of Science][Medline]
18. Balmain,A. and Nagase,H. (1998) Cancer resistance genes in mice: models for the study of tumour modifiers. Trends Genet., 14, 139–144.[Web of Science][Medline]
19. Nelles,E., Buetzler,C., Jung,D., Temme,A., Gabriel,H.D., Dahl,U., Traub,O., Stuempel,F., Jungermann,K., Zielasek,J., Toyka,K.V., Dermietzel,R. and Willecke,K. (1996) Defective propagation of signals generated by sympathetic nerve stimulation in the liver of connexin32-deficient mice. Proc. Natl Acad. Sci. USA, 93, 9565–9570.[Abstract/Free Full Text]
20. Wachstein,M. and Meisel,E. (1957) Histochemistry of hepatic phosphatases at a physiological pH. Am. J. Clin. Pathol., 27, 13–23.[Web of Science][Medline]
21. Schwarz,M., Buchmann,A., Schulte,M., Pearson,D. and Kunz,W. (1989) Heterogeneity of enzyme-altered foci in rat liver. Toxicol. Lett., 49, 297–317.[Web of Science][Medline]
22. Campbell,H.A., Pitot,H.C., Potter,V.R. and Laishes,B.A. (1982) Application of quantitative stereology to the evaluation of enzyme-altered foci in rat liver. Cancer Res., 42, 465–472.[Abstract/Free Full Text]
23. Hanigan,M.H., Kemp,C.J., Ginsler,J.J. and Drinkwater,N.R. (1988) Rapid growth of preneoplastic lesions in hepatocarcinogen-sensitive C3H/HeJ male mice relative to C57BL/6J male mice. Carcinogenesis, 9, 885–890.[Abstract/Free Full Text]

Received February 1, 1999; revised March 30, 1999; accepted March 30, 1999.

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				P. Marx-Stoelting, J. Mahr, T. Knorpp, S. Schreiber, M. F. Templin, T. Ott, A. Buchmann, and M. Schwarz Tumor Promotion in Liver of Mice with a Conditional Cx26 Knockout Toxicol. Sci., June 1, 2008; 103(2): 260 - 267. [Abstract] [Full Text] [PDF]

				F. Marongiu, S. Doratiotto, S. Montisci, P. Pani, and E. Laconi Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin? Am. J. Pathol., April 1, 2008; 172(4): 857 - 864. [Abstract] [Full Text] [PDF]

				N. Hokaiwado, M. Asamoto, K. Ogawa, and T. Shirai Transgenic Disruption of Gap Junctional Intercellular Communication Enhances Early but Not Late Stage Hepatocarcinogenesis in the Rat Toxicol Pathol, October 1, 2005; 33(6): 695 - 701. [Abstract] [Full Text] [PDF]

				T. J. King and P. D. Lampe The Gap Junction Protein Connexin32 Is a Mouse Lung Tumor Suppressor Cancer Res., October 15, 2004; 64(20): 7191 - 7196. [Abstract] [Full Text] [PDF]

				S. Aguilar, J. M. Corominas, N. Malats, J. A. Pereira, M. Dufresne, F. X. Real, and P. Navarro Tissue Plasminogen Activator in Murine Exocrine Pancreas Cancer: Selective Expression in Ductal Tumors and Contribution to Cancer Progression Am. J. Pathol., October 1, 2004; 165(4): 1129 - 1139. [Abstract] [Full Text] [PDF]

				T. J. King and P. D. Lampe Mice deficient for the gap junction protein Connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation Carcinogenesis, May 1, 2004; 25(5): 669 - 680. [Abstract] [Full Text] [PDF]

				M. L. Z. Dagli, H. Yamasaki, V. Krutovskikh, and Y. Omori Delayed liver regeneration and increased susceptibility to chemical hepatocarcinogenesis in transgenic mice expressing a dominant-negative mutant of connexin32 only in the liver Carcinogenesis, April 1, 2004; 25(4): 483 - 492. [Abstract] [Full Text] [PDF]

				J. C. SAEZ, V. M. BERTHOUD, M. C. BRANES, A. D. MARTINEZ, and E. C. BEYER Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions Physiol Rev, October 1, 2003; 83(4): 1359 - 1400. [Abstract] [Full Text] [PDF]

				O. Moennikes, S. Stahl, P. Bannasch, A. Buchmann, and M. Schwarz WY-14,643-mediated promotion of hepatocarcinogenesis in connexin32-wild-type and connexin32-null mice Carcinogenesis, September 1, 2003; 24(9): 1561 - 1565. [Abstract] [Full Text] [PDF]

				E. Leithe, V. Cruciani, T. Sanner, S.-O. Mikalsen, and E. Rivedal Recovery of gap junctional intercellular communication after phorbol ester treatment requires proteasomal degradation of protein kinase C Carcinogenesis, July 1, 2003; 24(7): 1239 - 1245. [Abstract] [Full Text] [PDF]

				J. L. Solan, M. D. Fry, E. M. TenBroek, and P. D. Lampe Connexin43 phosphorylation at S368 is acute during S and G2/M and in response to protein kinase C activation J. Cell Sci., June 1, 2003; 116(11): 2203 - 2211. [Abstract] [Full Text] [PDF]

				I. Kobsar, M. Berghoff, M. Samsam, C. Wessig, M. Maurer, K. V. Toyka, and R. Martini Preserved myelin integrity and reduced axonopathy in connexin32-deficient mice lacking the recombination activating gene-1 Brain, April 1, 2003; 126(4): 804 - 813. [Abstract] [Full Text] [PDF]

				M. Schwarz, I. Wanke, U. Wulbrand, O. Moennikes, and A. Buchmann Role of Connexin32 and {beta}-Catenin in Tumor Promotion in Mouse Liver Toxicol Pathol, January 1, 2003; 31(1): 99 - 102. [Abstract] [PDF]

				M. Evert, T. Ott, A. Temme, K. Willecke, and F. Dombrowski Morphology and morphometric investigation of hepatocellular preneoplastic lesions and neoplasms in connexin32-deficient mice Carcinogenesis, May 1, 2002; 23(5): 697 - 703. [Abstract] [Full Text] [PDF]

				T. Yano, F.-J. Hernandez-Blazquez, Y. Omori, and H. Yamasaki Reduction of malignant phenotype of HEPG2 cell is associated with the expression of connexin 26 but not connexin 32 Carcinogenesis, October 1, 2001; 22(10): 1593 - 1600. [Abstract] [Full Text] [PDF]

				S.-H. Jeong, S. S. M. Habeebu, and C. D. Klaassen Cadmium Decreases Gap Junctional Intercellular Communication in Mouse Liver Toxicol. Sci., September 1, 2000; 57(1): 156 - 166. [Abstract] [Full Text] [PDF]

				O. Moennikes, A. Buchmann, A. Romualdi, T. Ott, J. Werringloer, K. Willecke, and M. Schwarz Lack of Phenobarbital-mediated Promotion of Hepatocarcinogenesis in Connexin32-Null Mice Cancer Res., September 1, 2000; 60(18): 5087 - 5091. [Abstract] [Full Text]

				P. D. Lampe, E. M. TenBroek, J. M. Burt, W. E. Kurata, R. G. Johnson, and A. F. Lau Phosphorylation of Connexin43 on Serine368 by Protein Kinase C Regulates Gap Junctional Communication J. Cell Biol., June 26, 2000; 149(7): 1503 - 1512. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (36) Request Permissions Google Scholar Articles by Moennikes, O. Articles by Schwarz2, M. Search for Related Content PubMed PubMed Citation Articles by Moennikes, O. Articles by Schwarz2, M. Social Bookmarking          What's this?

Online ISSN 1460-2180 - Print ISSN 0143-3334

Copyright © 2009 Oxford University Press

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics