Keratinocyte Transglutaminase: Regulation and Release

  • R. H. Rice
  • R. Chakravarty
  • J. Chen
  • W. O’Callahan
  • A. L. Rubin
Part of the Advances in Experimental Medicine and Biology book series (NATO ASI F, volume 231)


Recent improvements in the serial culture of keratinocytes (Rheinwald, 1980; Allen-Hoffman and Rheinwald, 1984) now permit detailed analysis of the differentiation program in this cell type (Green, 1979). To study the program at a molecular level requires identification and characterization of specific marker proteins, regulation of whose synthesis and utilization are important in the cell function. In addition to the high content of keratin (and related cytoskeletal elements), the intracellular transglutaminase is responsible in part for the distinctive structural cohesiveness of mature squames. Thus, a critical feature of terminal differentiation is the formation of an envelope of cross-linked protein immediately beneath the plasma membrane, a transglutaminase-mediated process carried out by keratinocytes in culture (Sun and Green, 1976; Green, 1977; Rice and Green, 1977 and 1978). The cross-linking is elicited by elevation of calcium ion available to the enzyme and results in utilization of involucrin (Rice and Green, 1979; Simon and Green, 1985) and several other protein substrates (Simon and Green, 1984).


Terminal Differentiation Human Epidermal Keratinocytes Tissue Transglutaminase Transglutaminase Activity Retinyl Acetate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allen-Hoffman, B. L., and Rheinwald, J. G., 1984, Polycycllc aromatic hydrocarbon mutagenesis of human epidermal keratinocytes in culture., Proc. Natl. Acad. Sci. USA, 81:7802.CrossRefGoogle Scholar
  2. Banks-Schlegel, S., and Green, H., 1981, Involucrin synthesis and tissue assembly by keratinocytes in natural and cultured human epithelia, J. Cell Biol., 90:732.PubMedCrossRefGoogle Scholar
  3. Buxman, M. M., and Wuepper, K. D., 1976, Isolation, purification and characterization of bovine epidermal transglutaminase, Biochim. Biophys. Acta, 452:356.PubMedCrossRefGoogle Scholar
  4. Chung, S. I., 1972, Comparative studies on tissue transglutaminase and factor XIII, Ann. N. Y. Acad. Sci., 202:240.PubMedCrossRefGoogle Scholar
  5. Chung, S. I., and Folk, J. E., 1972, Transglutaminase from hair follicle of guinea pig, Proc. Natl. Acad. Sci. USA, 69:303.PubMedCrossRefGoogle Scholar
  6. Cline, P. R., and Rice, R. H., 1983, Modulation of involucrin and envelope competence in human keratinocytes by hydrocortisone, retinyl acetate and growth arrest, Cancer Res., 43:3203.PubMedGoogle Scholar
  7. Davies, P. J. A., Murtaugh, M. P., Moore, W. T., Johnson, G. S., and Lucas, D., 1985, Retinole acid-induced expression of tissue transglutaminase in human promyelocytic leukemia (HL-60) cells, J. Biol. Chem., 260:5166.PubMedGoogle Scholar
  8. Fuchs, E., and Green, H., 1981, Regulation of terminal differentiation of cultured keratinocytes by vitamin A, Cell, 25:617.PubMedCrossRefGoogle Scholar
  9. Green, H., 1977, Terminal differentiation of cultured human epidermal cells, Cell, 11:405.PubMedCrossRefGoogle Scholar
  10. Green, H., 1979, The keratinocyte as differentiated cell type, Harvey Lect., 74:101.Google Scholar
  11. Grundmann, U., Amann, E., Zettlmeissl, and Kupper, H. A., 1986, Characterization of cDNA coding for human factor XIIIa, Proc. Natl. Acad. Sci. USA, 83:8024.PubMedCrossRefGoogle Scholar
  12. Harding, H. W. J., and Rogers, G. E., 1972, Formation of the ε-(γ-glutamyl)-lysine cross-link in hair proteins: investigation of transamidases in hair follicles, Biochemistry, 11:2858.PubMedCrossRefGoogle Scholar
  13. Heimann, R., and Rice, R. H., 1983, Rat esophageal and epidermal keratinocytes: intrinsic differences in culture and derivation of continuous lines, J. Cell. Physiol., 117:362.PubMedCrossRefGoogle Scholar
  14. Hennings, H., Steinert, P., and Buxman, M. M., 1981, Calcium induction of transglutaminase and formation of ε-(γ-glutamyl)lysine cross-links in cultured mouse epidermal cells, Biochem. Biophys. Res. Commun., 102–739.Google Scholar
  15. Ichinose, A., Hendrickson, L. E., Fujikawa, K., and Davie, E. W., 1986, Amino acid sequence of the a subunit of human factor XIII, Biochemistry, 25:6900.PubMedCrossRefGoogle Scholar
  16. Jetten, A. M., and Shirley, J. E., 1986, Characterization of transglutaminase activity in rabbit tracheal epithelial cells: regulation by retinoids, J. Biol. Chem., 261:15097.PubMedGoogle Scholar
  17. Lichti, U., Ben, T., and Yuspa, S. H., 1985, Retinolc acid induced transglutaminase is distinct from epidermal transglutaminase, J. Biol. Chem., 260:1422.PubMedGoogle Scholar
  18. Moore, W. T., Murtaugh, M. P., and Davies, P. J. A., 1984, Retinolc acidinduced expression of tissue transglutaminase in mouse peritoneal macrophages, J. Biol. Chem., 259:12794.PubMedGoogle Scholar
  19. Negi, M., Colbert, M. C., and Goldsmith, L. A., 1985, High molecular weight epidermal transglutaminase, J. Invest. Dermatol., 85:75.PubMedCrossRefGoogle Scholar
  20. Parenteau, N. L., Pilato, A., and Rice, R. H., 1986, Induction of keratinocyte type I transglutaminase in epithelial cells of the rat, Differentiation, 33:130.PubMedCrossRefGoogle Scholar
  21. Peterson, L. L., and Wuepper, K. D., 1984, Epidermal and hair follicle transglutaminases and cross-linking in skin, Molec. Cell. Biochem., 58:99.PubMedCrossRefGoogle Scholar
  22. Phillips, M. A., and Rice, R. H., 1983, Convergent differentiation in cultured rat cells from nonkeratinized epithelia: keratinocyte character and intrinsic differences, J. Cell Biol., 97:686.PubMedCrossRefGoogle Scholar
  23. Rheinwald, J. G., 1980, Serial cultivation of normal human epidermal keratinocytes, Methods Cell Biol., 21:229.Google Scholar
  24. Rheinwald, J. G., and Beckett, M. A., 1980, Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes, Cell, 22:629.PubMedCrossRefGoogle Scholar
  25. Rheinwald, J. G., and Beckett, M. A., 1981, Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultured from human squamous cell carcinomas, Cancer Res., 41:1657.PubMedGoogle Scholar
  26. Rice, R. H., and Cline, P. R., 1984, Opposing effects of 2,3,7,8-tetra-chlorodibenzo-p-dioxin and hydrocortisone on growth and differentiation of cultured malignant human keratinocytes, Carcinogenesis, 5:367.PubMedCrossRefGoogle Scholar
  27. Rice, R. H., and Green, H., 1977, The cornified envelope of terminally differentiated human epidermal keratinocytes consists of cross-linked protein, Cell, 11:417.PubMedCrossRefGoogle Scholar
  28. Rice, R. H., and Green, H., 1978, Relationship of protein synthesis and transglutaminase activity to formation of the cross-linked envelope during terminal differentiation of the cultured human epidermal keratinocyte, J. Cell Biol., 76:705.PubMedCrossRefGoogle Scholar
  29. Rice, R. H., and Green, H., 1979, Presence in human epidermal cells of a soluble protein precursor of the cross-linked envelope: activation of the cross-linking by calcium ions, Cell, 18:681.PubMedCrossRefGoogle Scholar
  30. Rice, R. H., and Levine, L., 1984, Melittin-stimulated arachidonic acid metabolism by cultured malignant human epidermal keratinocytes, Biochem. Biophys. Res. Commun., 124:303.PubMedCrossRefGoogle Scholar
  31. Rice, R. H., and Thacher, S. M., 1986, Involucrin: a constituent of crosslinked envelopes and marker of squamous maturation, in: “Biology of the Integument,” J. Bereiter-Hahn, A. G. Matoltsy, K. S. Richards, eds., Springer-Verlag, Berlin Heidelberg.Google Scholar
  32. Rothblatt, G. H., Arbogast, L. Y., Ouellette, L., and Howard, B. V., 1975, Preparation of delipidized serum for use in cell culture systems, In Vitro, 11:354.CrossRefGoogle Scholar
  33. Rubin, A. L., and Rice, R. H., 1986, Differential regulation by retinoic acid and calcium of transglutaminases in cultured neoplastic and normal human keratinocytes, Cancer Res., 46:2356.PubMedGoogle Scholar
  34. Sun, T.-T., and Green, H., 1976, Differentiation of the epidermal keratinocyte in cell culture: formation of the cornified envelope, Cell, 9:511.PubMedCrossRefGoogle Scholar
  35. Simon, M., and Green, H., 1984, Participation of membrane-associated proteins in the formation of the cross-linked envelope of the keratinocyte, Cell, 36:327.CrossRefGoogle Scholar
  36. Simon, M., and Green, H., 1985, Enzymatic cross-linking of involucrin and other proteins by keratinocyte particulates in vitro, Cell, 40:677.PubMedCrossRefGoogle Scholar
  37. Takahashi, N., Takahashi, Y., and Putnam, F. W., 1986, Primary structure of blood coagulation factor XIIIa (fibrinoligase, transglutaminase) from human placenta, Proc. Natl. Acad. Sci. USA, 83:8019.PubMedCrossRefGoogle Scholar
  38. Thacher, S. M., and Rice, R. H., 1985, Keratinocyte-specific transglutaminase of cultured human epidermal cells: relation to cross-linked envelope formation and terminal differentiation, Cell, 40:685.PubMedCrossRefGoogle Scholar
  39. Thacher, S. M., Coe, E. L., and Rice, R. H., 1985, Retinoid suppression of transglutaminase activity and envelope competence in cultured human epidermal carcinoma cells: hydrocortisone is a potent antagonist of retinyl acetate but not retinoic acid, Differentiation, 29:82.PubMedCrossRefGoogle Scholar
  40. Tosteson, M. T., and Tosteson, D. C., 1981, The sting: melittin forms channels in lipid bilayers, Biophys. J., 36:109.PubMedCrossRefGoogle Scholar
  41. Warhol, M. J., Roth, J., Lucocq, J. M., Pinkus, G. S., and Rice, R. H., 1985, Immuno-ultrastructural localization of involucrin in squamous epithelium and cultured keratinocytes, J. Histochem. Cytochem., 33:141.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • R. H. Rice
    • 1
  • R. Chakravarty
    • 1
  • J. Chen
    • 1
  • W. O’Callahan
    • 1
  • A. L. Rubin
    • 1
  1. 1.Laboratory of ToxicologyHarvard School of Public HealthBostonUSA

Personalised recommendations