Human Pathology
Volume 36, Issue 5 , Pages 536-545 , May 2005

The phosphorylated form of connexin43 is up-regulated in breast hyperplasias and carcinomas and in their neoformed capillaries

  • Victor E. Gould, MD

      Affiliations

    • Department of Pathology, Rush Medical College, Chicago, Ill 60611, USA
    • Corresponding Author InformationCorresponding author.
  • ,
  • Juan Miguel Mosquera, MD

      Affiliations

    • Department of Pathology, Rush Medical College, Chicago, Ill 60611, USA
  • ,
  • Kerstin Leykauf, BSc

      Affiliations

    • German Cancer Research Center, D-62109 Heidelberg, Germany
  • ,
  • Paolo Gattuso, MD

      Affiliations

    • Department of Pathology, Rush Medical College, Chicago, Ill 60611, USA
  • ,
  • Matthias Dürst, PhD

      Affiliations

    • Women's Clinic, University of Jena, D-07740 Jena, Germany
  • ,
  • Angel Alonso, PhD

      Affiliations

    • German Cancer Research Center, D-62109 Heidelberg, Germany

References 

  1. Bruzzone R, White TW, Paul DL. Connexions with connexins: the molecular basis of direct intercellular signaling. Eur J Biochem. 1996;238:1–27
  2. Kumar NM, Gilula NB. The gap junction communication channel. Cell. 1996;84:381–388
  3. Goodenough DA, Goliger JA, Paul DL. Connexins, connexons and intercellular communication. Annu Rev Biochem. 1996;65:475–502
  4. Unger VM, Kumar NM, Gilula NB, Yeager M. Three dimensional structure of a recombinant gap junction membrane channel. Science. 1999;283:1176–1180
  5. Willecke K, Eiberger J, Degen J, Eckhardt D, Romualdi A, Guldenagel M, et al. Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem. 2002;383:725–737
  6. Lampe PD, Lau AF. Regulation of gap junctions by phosphorylation of connexins. Arch Biochem Biophys. 2000;384:205–215
  7. Monaghan P, Clarke C, Perusinghe NP, Moss DW, Chen X-Y, Evans WH. Gap junction distribution and connexin expression in the human breast. Exp Cell Res. 1996;223:29–38
  8. Monaghann P, Perusinghe N, Carlile G, Evans WH. Rapid modulation of gap junction expression in mouse mammary gland during pregnancy, lactation and involution. J Histochem Cytochem. 1994;42:931–938
  9. Hendrix EM, Myatt L, Sellers S, Russell PT, Larsen WJ. Steroid hormone regulation of rat myometrial gap junction formation: effects on Cx43 levels and trafficking. Biol Reprod. 1995;52:457–560
  10. Tsai H, Werber J, Davia MO, Edelman M, Tanaka KE, Melman A, et al. Reduced connexin 43 expression in high grade human prostatic adenocarcinoma cells. Biochem Biophys Res Commun. 1996;227:64–69
  11. Hanna EA, Umhauer S, Roshong SL, Piechocki MP, Fernstrom MJ, Fanning JD, et al. Gap junction intercellular communication and connexin43 expression in human ovarian surface epithelial cells and ovarian carcinomas in vivo and in vitro. Carcinogenesis. 1999;20:1369–1373
  12. King TJ, Fukushima LH, Hieber AD, Shimabukuro KA, Sakr WA, Bertram JS. Reduced levels of connexin43 in cervical dysplasia: inducible expression in a cervical carcinoma cell line decreases neoplastic potential with implications for tumor progression. Carcinogenesis. 2000;21:1097–1109
  13. Tada J, Hashimoto K. Ultrastructural localization of gap junction protein connexin 43 in normal human skin, basal cell carcinoma, and squamous cell carcinoma. J Cutan Pathol. 1997;24:628–635
  14. Laird DW, Fistouris P, Batist G, Alpert L, Huynh HAT, Carystinos GD, et al. Deficiency of connexin43 gap junctions is an independent marker for breast tumors. Cancer Res. 1999;59:4104–4110
  15. Jamieson S, Going JJ, D'Arcy R, George WD. Expression of gap junction protein connexin 26 and connexin 43 in normal human breast and in breast tumors. J Pathol. 1998;184:37–43
  16. Leykauf K, Duerst M, Alonso A. Phosphorylation and subcellular distribution of connexin43 in normal and stressed cells. Cell Tissue Res. 2003;311:23–30
  17. Musil LS, Goodenough DA. Biochemical analysis of connexin43 intracellular transport, phosphorylation, and assembly into gap junctions. J Cell Biol. 1991;115:1357–1374
  18. Gould VE, Shin SS, Manderino GL, Rittenhouse HG, Tomita JT, Gooch GT. Selective expression of a novel mucin-type glycoprotein in human tumors. Hum Pathol. 1988;19:623–627
  19. Koukoulis GK, Gould VE, Bhattacharya A, Gould JE, Howeedy AA, Virtanen I. Tenascin in normal, hyperplastic and neoplastic tissues. Hum Pathol. 1991;22:636–643
  20. Gould VE, Orucevic A, Zentgraf H-W, Gattuso P, Martinez N, Alonso A. Nup 88(karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis. Hum Pathol. 2002;33:534–536
  21. Hsu SM, Raine L, Fanger H. Use of the avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem. 1981;29:577–580
  22. Moll R, Lee I, Gould VE, Berndt R, Roessner A, Franke WW. Immunohistochemical analysis of Ewing's tumors: patterns of intermediate filaments and desmosomal proteins indicate cell type heterogeneity and pluripotential differentiation. Am J Pathol. 1987;127:288–304
  23. Gould VE, Snyder RW. Ultrastructural features of papillomatosis and carcinoma of nipple ducts. The significance of myoepithelial cells and basal lamina in benign, “questionable” and malignant lesions. Pathol Annu. 1974;9:441–474
  24. Gould VE, Jao W, Battifora H. Ultrastructural analysis in the differential diagnosis of breast tumors. The significance of myoepithelial cells, basal lamina, intracytoplasmic lumina and secretory granules. Pathol Res Pract. 1980;167:45–70
  25. Nagle RB, Boecker W, Davis JR, Heid HW, Kaufmann M, Lucas DO, et al. Characterization of breast carcinomas by two monoclonal antibodies distinguishing myoepithelial from luminal cells. J Histochem Cytochem. 1986;34:869–881
  26. Jarasch E-D, Nagle RB, Kaufmann M, Maurer C, Boecker WJ. Differential diagnosis of benign epithelial cell proliferations and carcinomas of the breast using antibodies to cytokeratins. Hum Pathol. 1988;19:276–289
  27. Gould VE, Koukoulis GK, Jansson DS, Nagle RB, Franke WW, Moll R. Coexpression patterns of vimentin and glial filament protein with cytokeratins in the normal, hyperplastic and neoplastic breast. Am J Pathol. 1990;137:1143–1151
  28. Gould VE, Miller J, Jao W. Ultrastructure of medullary, intraductal, tubular and adenocystic carcinoma. Comparative patterns of myoepithelial differentiation and basal lamina deposition. Am J Pathol. 1975;78:401–416
  29. Kanemitsu MY, Loo LW, Simon A, Lau AF, Eckhart W. Tyrosine phosphorylation of connexin43 by v-Src is mediated by SH2 and SH3 domain interactions. J Biol Chem. 1997;272:22824–22831
  30. Zhou L, Kasperek EM, Nicholson BJ. Dissection of the molecular basis of pp60(v-src) induced gating of connexin 43 gap junction channels. J Cell Biol. 1999;144:1033–1045
  31. Giepmans BNG, Hengeveld T, Postma FR, Moolenaar WH. Interaction of c-Src with gap junction connexin-43. J Biol Chem. 2001;276:8544–8549
  32. Lampe PD, TenBroek EM, Burt JM, Kurata WE, Johnson RG, Lau AF. Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication. J Cell Biol. 2000;149:1503–1512
  33. Kanemitsu MY, Lau AF. Epidermal growth factor stimulates the disruption of gap junction communication and connexin43 phosphorylation independent of 12-0-tetradecanoylphorbol 13-acetate-sensitive protein kinase C: the possible involvement of mitogen-activated kinase. Mol Biol Cell. 1993;4:837–848
  34. Warn-Cramer BJ, Lampe PD, Kurata WE, Kanemitsu NY, Loo LW, Eckhart W, et al. Characterization of the mitogen-activated protein kinase phosphorylation sites on the connexin-43 gap junction protein. J Biol Chem. 1996;271:3779–3786
  35. Warn-Cramer BJ, Cottrell GT, Burt JM, Lau AF. Regulation of connexin-43 gap junctional intercellular communication by mitogen-activated protein kinase. J Biol Chem. 1998;273:9188–9196
  36. Nahta R, Hortobagyi N, Esteva FJ. Growth factor receptors on breast cancer: potential for therapeutic intervention. Oncologist. 2003;8:5–17
  37. Hossain MZ, Ao P, Boynton AL. Platelet-derived growth factor-induced disruption of gap junctional communication and phosphorylation of connexin 43 involves protein kinase C and mitogen-activated protein kinase. J Cell Physiol. 1998;176:332–341
  38. Van Rijen HV, van Kempen MJ, Postma S, Jongsma HJ. Tumor necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine. 1998;10:258–264
  39. Van Kempen MJ, Jongsma HJ. Distribution of connexin 37, connexin 40 and connexin 43 in the aorta and coronary artery of several mammals. Histochem Cell Biol. 1999;112:479–486
  40. Yeh HI, Lai YJ, Chang HM, Ko YS, Severs NJ, Tsai CH. Multiple connexin expression in regenerating arterial endothelial gap junctions. Arterioscler Thromb Vasc Biol. 2000;20:1753–1762
  41. Sato T, Haimovici R, Kao R, An-Fei L, Roy S. Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells. Diabetes. 2000;51:1565–1571
  42. Xie H-Q, Laird DW, Chang T-H, Hu VW. A mitosis-specific phosphorylation of the gap junction protein connexin43 in human vascular cells: biochemical characterization and localization. J Cell Biol. 1997;137:203–210
  43. Gould VE, Wagner BM. Angiogenesis: an expanding universe. Hum Path. 2002;33:1061–1063
  44. Scappaticci FA. Mechanisms and future directions for angiogenesis-based cancer therapies. J Clin Oncol. 2002;20:3906–3927
  45. Zhang W, Nwagwu C, Le DM, Yong VW, Song H, Couldwell WT. Increased invasive capacity of connexin-43 malignant glioma cells. J Neurosurg. 2003;99:1039–1046

PII: S0046-8177(05)00164-4

doi: 10.1016/j.humpath.2005.03.013

Human Pathology
Volume 36, Issue 5 , Pages 536-545 , May 2005