Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

Oncogene volume 24, pages 1718–1726 (2005)Cite this article

Abstract

Connexin32 knockout mice (Cx32-KO) exhibit increased chemical- and radiation-induced liver and lung tumor formation with many lung tumors demonstrating decreased levels of the tumor suppressor p27KIP1. To determine if p27 deficiency alters Cx32-influenced tumorigenesis, we have generated a Cx32/p27 double-deficient mouse strain (DKO) and show here that exposure of these mice to X-ray radiation resulted in an increase or decrease in tumorigenesis depending on the tissue. Several tissues were highly sensitive to loss of p27 tumor suppressor function (intestine, adrenal, pituitary) resulting in an increased overall tumor burden in DKO mice compared to both wild-type (P<0.005) and Cx32-KO mice (P=0.066). However, additional deletion of p27 in a Cx32-KO background resulted in a statistically significant decrease in the liver tumor incidence suggesting that Cx32 and p27 pathways mechanistically interact. Immunohistochemical analysis revealed an increased percentage of Cx32-KO liver and lung tumors harboring active mitogen-activated protein kinase (Erk1, Erk2) pathways in contrast to lower percentages of activated wild-type (P<0.005) and DKO tumors (P=0.027). Increased MAPK activation in liver tumors did not correlate with Ha-ras codon-61 mutation status. This study demonstrates that tissues dependent on Cx32 tumor suppression, such as the liver and lung, exhibit altered tumorigenesis and tumor biology (MAPK pathway activation) related to p27 status.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Abraham V, Chou ML, George P, Pooler P, Zaman A, Savani RC and Koval M . (2001). Am. J. Physiol. – Lung Cell. Mol. Physiol., 280, L1085–1093.

  • Avanzo JL, Mesnil M, Hernandez-Blazquez FJ, Mackowiak II, Mori CM, Da Silva TC, Oloris SC, Garate AP, Massironi SM, Yamasaki H and Dagli ML . (2004). Carcinogenesis, 25, 1973–1982.

  • Aydinlik H, Nguyen TD, Moennikes O, Buchmann A and Schwarz M . (2001). Oncogene., 20, 7812–7816.

  • Defamie N, Berthaut I, Mograbi B, Chevallier D, Dadoune JP, Fenichel P, Segretain D and Pointis G . (2003). Lab. Invest., 83, 449–456.

  • Evert M, Ott T, Temme A, Willecke K and Dombrowski F . (2002). Carcinogenesis, 23, 697–703.

  • Fero ML, Randel E, Gurley KE, Roberts JM and Kemp CJ . (1998). Nature, 396, 177–180.

  • Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K and Roberts JM . (1996). Cell, 85, 733–744.

  • Hanna EA, Umhauer S, Roshong SL, Piechocki MP, Fernstrom MJ, Fanning JD and Ruch RJ . (1999). Carcinogenesis, 20, 1369–1373.

  • King TJ, Fukushima LH, Hieber AD, Shimabukuro KA, Sakr WA and Bertram JS . (2000). Carcinogenesis, 21, 1097–1109.

  • King TJ, Fukushima LH, Yasui Y, Lampe PD and Bertram JS . (2002). Mol. Carcinogen., 35, 29–41.

  • King TJ and Lampe PD . (2004a). Cancer Res., 64, 7191–7196.

  • King TJ and Lampe PD . (2004b). Carcinogenesis, 25, 669–680.

  • Koffler L, Roshong S, Kyu Park I, Cesen-Cummings K, Thompson DC, Dwyer-Nield LD, Rice P, Mamay C, Malkinson AM and Ruch RJ . (2000). J. Cell. Biochem., 79, 347–354.

  • Koval M . (2002). Am. J. Physiol. – Lung Cell. Mol. Physiol., 283, L875–L893.

  • Krutovskikh V and Yamasaki H . (2000). Mutat. Res., 462, 197–207.

  • Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC and Scheithauer BW . (1999). Am. J. Pathol., 154, 313–323.

  • Lo CW . (1999). Dev. Genet., 24, 1–4.

  • Lumniczky K, Antal S, Unger E, Wunderlich L, Hidvegi EJ and Safrany G . (1998). Mol. Carcinogen., 21, 100–110.

  • Maronpot RR . (1999). Pathology of the Mouse 1st edn. Cache River Press: Vienna, IL.

    Google Scholar 

  • Mehta PP, Perez-Stable C, Nadji M, Mian M, Asotra K and Roos BA . (1999). Dev. Genet., 24, 91–110.

  • Mesnil M . (2002). Biol. Cell., 94, 493–500.

  • Moennikes O, Buchmann A, Ott T, Willecke K and Schwarz M . (1999). Carcinogenesis, 20, 1379–1382.

  • Muraoka RS, Lenferink AE, Simpson J, Brantley DM, Roebuck LR, Yakes FM and Arteaga CL . (2001). J. Cell. Biol., 153, 917–932.

  • Nelles E, Butzler C, Jung D, Temme A, Gabriel HD, Dahl U, Traub O, Stumpel F, Jungermann K, Zielasek J, Toyka KV, Dermietzel R and Willecke K . (1996). Proc. Natl. Acad. Sci. USA, 93, 9565–9570.

  • Philipp-Staheli J, Kim KH, Liggitt D, Gurley KE, Longton G and Kemp CJ . (2004). Oncogene, 23, 905–913.

  • Philipp-Staheli J, Kim KH, Payne SR, Gurley KE, Liggitt D, Longton G and Kemp CJ . (2002). Cancer Cell, 1, 355–368.

  • Philipp-Staheli J, Payne SR and Kemp CJ . (2001). Exp. Cell Res., 264, 148–168.

  • Ramakrishna G, Perella C, Birely L, Diwan BA, Fornwald LW and Anderson LM . (2002). Toxicol. Appl. Pharmacol., 179, 21–34.

  • Richard G . (2001). Adv. Dermatol., 17, 243–277.

  • Ruch RJ, Cesen-Cummings K and Malkinson AM . (1998). Exp. Lung Res., 24, 523–539.

  • Scherer SS, Xu YT, Nelles E, Fischbeck K, Willecke K and Bone LJ . (1998). GLIA, 24, 8–20.

  • Schwarz M, Wanke I, Wulbrand U, Moennikes O and Buchmann A . (2003). Toxicol. Pathol., 31, 99–102.

  • Sherr CJ and Roberts JM . (1999). Genes Dev., 13, 1501–1512.

  • Temme A, Buchman A, Babriel HC, Nelles E, Scharz M and Willecke K . (1997). Curr. Biol., 7, 713–718.

  • Temme A, Stumpel F, Sohl G, Rieber EP, Jungermann K, Willecke K and Ott T . (2001). Pflugers Archiv – Eur. J. Physiol., 442, 961–966.

  • Trosko JE and Ruch RJ . (1998). Front. Biosci., 3, 208–236.

  • Upham BL, Rummel AM, Carbone JM, Trosko JE, Ouyang Y, Crawford RB and Kaminski NE . (2003). Int. J. Cancer, 104, 12–18.

  • Warn-Cramer BJ, Cottrell GT, Burt JM and Lau AF . (1998). J. Biol. Chem., 273, 9188–9196.

  • Warn-Cramer BJ, Lampe PD, Kurata WE, Kanemitsu MY, Loo LWM, Eckhart W and Lau AF . (1996). J. Biol. Chem., 271, 3779–3786.

  • Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi R, Guldenagel M, Deutsch U and Sohl G . (2002). Biol. Chem., 383, 725–737.

  • Yao R, Wang Y, Lubet RA and You M . (2003). Neoplasia (New York), 5, 41–52.

  • Zhang YW, Morita I, Ikeda M, Ma KW and Murota S . (2001). Oncogene, 20, 4138–4149.

  • Zhang YW, Nakayama K and Morita I . (2003). Cancer Res., 63, 1623–1630.

Download references

Acknowledgements

Thanks to Steven Scherer (Philadelphia, PA, USA) for providing Cx32-KO mice. This work was supported by NIH Grants AR47963, GM55632 (PDL). TJK was a recipient of an Institutional NIH-T32 Postdoctoral Research Training Grant (T32-AI07509).

Author information

Authors and Affiliations

  1. Cancer Prevention Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    Timothy J King, JoAnn Prunty, Jung-Lim Shin & Paul D Lampe

  2. Department of Pathobiology, University of Washington, Seattle, WA, 98195, USA

    Timothy J King & Paul D Lampe

  3. Cancer Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    Kay E Gurley & Christopher J Kemp

Authors
  1. Timothy J King
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kay E Gurley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. JoAnn Prunty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jung-Lim Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher J Kemp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul D Lampe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy J King.

Rights and permissions

Reprints and permissions

About this article

Cite this article

King, T., Gurley, K., Prunty, J. et al. Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner. Oncogene 24, 1718–1726 (2005). https://doi.org/10.1038/sj.onc.1208355

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208355

Keywords

This article is cited by

Search

Advanced search

Quick links