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. 1994 Feb 1;91(3):873–877. doi: 10.1073/pnas.91.3.873

Oncogene activation of human keratin 18 transcription via the Ras signal transduction pathway.

R Pankov 1, A Umezawa 1, R Maki 1, C J Der 1, C A Hauser 1, R G Oshima 1
PMCID: PMC521414  PMID: 7508123

Abstract

Keratin 8 (K8) and keratin 18 (K18) are intermediate filament proteins normally expressed in simple epithelial tissues and persistently expressed in a wide variety of carcinomas. Ectopic expression of K8 and K18 occurs in some epidermal and murine skin carcinomas induced by chemical carcinogenesis or oncogenic ras expression. We show here that K18 is a direct target of the Ras signal transduction pathway, by demonstrating that activated Ha-Ras, as well as activated Src, Lck, or Raf, stimulates the transcription of K18. This activation is mediated by an enhancer element containing essential and closely spaced Ets and AP-1 transcription factor binding sites. Oncogene activation of K18 transcription provides a molecular explanation for the persistent and sometimes unexpected expression of K18 in such a wide variety of tumors.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abe M., Oshima R. G. A single human keratin 18 gene is expressed in diverse epithelial cells of transgenic mice. J Cell Biol. 1990 Sep;111(3):1197–1206. doi: 10.1083/jcb.111.3.1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aoyama A., Klemenz R. Oncogene-mediated effects on cellular gene expression. Crit Rev Oncog. 1993;4(1):53–94. [PubMed] [Google Scholar]
  3. Binétruy B., Smeal T., Karin M. Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain. Nature. 1991 May 9;351(6322):122–127. doi: 10.1038/351122a0. [DOI] [PubMed] [Google Scholar]
  4. Bortner D. M., Langer S. J., Ostrowski M. C. Non-nuclear oncogenes and the regulation of gene expression in transformed cells. Crit Rev Oncog. 1993;4(2):137–160. [PubMed] [Google Scholar]
  5. Caulín C., Bauluz C., Gandarillas A., Cano A., Quintanilla M. Changes in keratin expression during malignant progression of transformed mouse epidermal keratinocytes. Exp Cell Res. 1993 Jan;204(1):11–21. doi: 10.1006/excr.1993.1003. [DOI] [PubMed] [Google Scholar]
  6. Cheng C., Kilkenny A. E., Roop D., Yuspa S. H. The v-ras oncogene inhibits the expression of differentiation markers and facilitates expression of cytokeratins 8 and 18 in mouse keratinocytes. Mol Carcinog. 1990;3(6):363–373. doi: 10.1002/mc.2940030608. [DOI] [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Chu Y. W., Runyan R. B., Oshima R. G., Hendrix M. J. Expression of complete keratin filaments in mouse L cells augments cell migration and invasion. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4261–4265. doi: 10.1073/pnas.90.9.4261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Debus E., Moll R., Franke W. W., Weber K., Osborn M. Immunohistochemical distinction of human carcinomas by cytokeratin typing with monoclonal antibodies. Am J Pathol. 1984 Jan;114(1):121–130. [PMC free article] [PubMed] [Google Scholar]
  10. Diaz-Guerra M., Haddow S., Bauluz C., Jorcano J. L., Cano A., Balmain A., Quintanilla M. Expression of simple epithelial cytokeratins in mouse epidermal keratinocytes harboring Harvey ras gene alterations. Cancer Res. 1992 Feb 1;52(3):680–687. [PubMed] [Google Scholar]
  11. Farnsworth C. L., Feig L. A. Dominant inhibitory mutations in the Mg(2+)-binding site of RasH prevent its activation by GTP. Mol Cell Biol. 1991 Oct;11(10):4822–4829. doi: 10.1128/mcb.11.10.4822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Granger-Schnarr M., Benusiglio E., Schnarr M., Sassone-Corsi P. Transformation and transactivation suppressor activity of the c-Jun leucine zipper fused to a bacterial repressor. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4236–4239. doi: 10.1073/pnas.89.10.4236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gutman A., Wasylyk B. The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites. EMBO J. 1990 Jul;9(7):2241–2246. doi: 10.1002/j.1460-2075.1990.tb07394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hendrix M. J., Seftor E. A., Chu Y. W., Seftor R. E., Nagle R. B., McDaniel K. M., Leong S. P., Yohem K. H., Leibovitz A. M., Meyskens F. L., Jr Coexpression of vimentin and keratins by human melanoma tumor cells: correlation with invasive and metastatic potential. J Natl Cancer Inst. 1992 Feb 5;84(3):165–174. doi: 10.1093/jnci/84.3.165. [DOI] [PubMed] [Google Scholar]
  15. Jones K. A., Yamamoto K. R., Tjian R. Two distinct transcription factors bind to the HSV thymidine kinase promoter in vitro. Cell. 1985 Sep;42(2):559–572. doi: 10.1016/0092-8674(85)90113-8. [DOI] [PubMed] [Google Scholar]
  16. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  17. Knapp A. C., Bosch F. X., Hergt M., Kuhn C., Winter-Simanowski S., Schmid E., Regauer S., Bartek J., Franke W. W. Cytokeratins and cytokeratin filaments in subpopulations of cultured human and rodent cells of nonepithelial origin: modes and patterns of formation. Differentiation. 1989 Dec;42(2):81–102. doi: 10.1111/j.1432-0436.1989.tb00610.x. [DOI] [PubMed] [Google Scholar]
  18. Knapp A. C., Franke W. W. Spontaneous losses of control of cytokeratin gene expression in transformed, non-epithelial human cells occurring at different levels of regulation. Cell. 1989 Oct 6;59(1):67–79. doi: 10.1016/0092-8674(89)90870-2. [DOI] [PubMed] [Google Scholar]
  19. Kulesh D. A., Oshima R. G. Cloning of the human keratin 18 gene and its expression in nonepithelial mouse cells. Mol Cell Biol. 1988 Apr;8(4):1540–1550. doi: 10.1128/mcb.8.4.1540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Langer S. J., Bortner D. M., Roussel M. F., Sherr C. J., Ostrowski M. C. Mitogenic signaling by colony-stimulating factor 1 and ras is suppressed by the ets-2 DNA-binding domain and restored by myc overexpression. Mol Cell Biol. 1992 Dec;12(12):5355–5362. doi: 10.1128/mcb.12.12.5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lloyd A., Yancheva N., Wasylyk B. Transformation suppressor activity of a Jun transcription factor lacking its activation domain. Nature. 1991 Aug 15;352(6336):635–638. doi: 10.1038/352635a0. [DOI] [PubMed] [Google Scholar]
  22. Markey A. C., Lane E. B., Churchill L. J., MacDonald D. M., Leigh I. M. Expression of simple epithelial keratins 8 and 18 in epidermal neoplasia. J Invest Dermatol. 1991 Nov;97(5):763–770. doi: 10.1111/1523-1747.ep12486607. [DOI] [PubMed] [Google Scholar]
  23. Miettinen M., Franssila K. Immunohistochemical spectrum of malignant melanoma. The common presence of keratins. Lab Invest. 1989 Dec;61(6):623–628. [PubMed] [Google Scholar]
  24. Miller A. D., Law M. F., Verma I. M. Generation of helper-free amphotropic retroviruses that transduce a dominant-acting, methotrexate-resistant dihydrofolate reductase gene. Mol Cell Biol. 1985 Mar;5(3):431–437. doi: 10.1128/mcb.5.3.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moll R., Franke W. W., Schiller D. L., Geiger B., Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. doi: 10.1016/0092-8674(82)90400-7. [DOI] [PubMed] [Google Scholar]
  26. Neznanov N. S., Oshima R. G. cis regulation of the keratin 18 gene in transgenic mice. Mol Cell Biol. 1993 Mar;13(3):1815–1823. doi: 10.1128/mcb.13.3.1815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nye J. A., Petersen J. M., Gunther C. V., Jonsen M. D., Graves B. J. Interaction of murine ets-1 with GGA-binding sites establishes the ETS domain as a new DNA-binding motif. Genes Dev. 1992 Jun;6(6):975–990. doi: 10.1101/gad.6.6.975. [DOI] [PubMed] [Google Scholar]
  28. Oshima R. G., Abrams L., Kulesh D. Activation of an intron enhancer within the keratin 18 gene by expression of c-fos and c-jun in undifferentiated F9 embryonal carcinoma cells. Genes Dev. 1990 May;4(5):835–848. doi: 10.1101/gad.4.5.835. [DOI] [PubMed] [Google Scholar]
  29. Oshima R. G., Trevor K., Shevinsky L. H., Ryder O. A., Ceceña G. Identification of the gene coding for the Endo B murine cytokeratin and its methylated, stable inactive state in mouse nonepithelial cells. Genes Dev. 1988 May;2(5):505–516. doi: 10.1101/gad.2.5.505. [DOI] [PubMed] [Google Scholar]
  30. Reddy M. A., Langer S. J., Colman M. S., Ostrowski M. C. An enhancer element responsive to ras and fms signaling pathways is composed of two distinct nuclear factor binding sites. Mol Endocrinol. 1992 Jul;6(7):1051–1060. doi: 10.1210/mend.6.7.1324418. [DOI] [PubMed] [Google Scholar]
  31. Reynolds P. J., Hurley T. R., Sefton B. M. Functional analysis of the SH2 and SH3 domains of the lck tyrosine protein kinase. Oncogene. 1992 Oct;7(10):1949–1955. [PubMed] [Google Scholar]
  32. Schaafsma H. E., Ramaekers F. C., van Muijen G. N., Lane E. B., Leigh I. M., Robben H., Huijsmans A., Ooms E. C., Ruiter D. J. Distribution of cytokeratin polypeptides in human transitional cell carcinomas, with special emphasis on changing expression patterns during tumor progression. Am J Pathol. 1990 Feb;136(2):329–343. [PMC free article] [PubMed] [Google Scholar]
  33. Schüssler M. H., Skoudy A., Ramaekers F., Real F. X. Intermediate filaments as differentiation markers of normal pancreas and pancreas cancer. Am J Pathol. 1992 Mar;140(3):559–568. [PMC free article] [PubMed] [Google Scholar]
  34. Stanton V. P., Jr, Nichols D. W., Laudano A. P., Cooper G. M. Definition of the human raf amino-terminal regulatory region by deletion mutagenesis. Mol Cell Biol. 1989 Feb;9(2):639–647. doi: 10.1128/mcb.9.2.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Steinert P. M., Roop D. R. Molecular and cellular biology of intermediate filaments. Annu Rev Biochem. 1988;57:593–625. doi: 10.1146/annurev.bi.57.070188.003113. [DOI] [PubMed] [Google Scholar]
  36. Trask D. K., Band V., Zajchowski D. A., Yaswen P., Suh T., Sager R. Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2319–2323. doi: 10.1073/pnas.87.6.2319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Urness L. D., Thummel C. S. Molecular interactions within the ecdysone regulatory hierarchy: DNA binding properties of the Drosophila ecdysone-inducible E74A protein. Cell. 1990 Oct 5;63(1):47–61. doi: 10.1016/0092-8674(90)90287-o. [DOI] [PubMed] [Google Scholar]
  38. Wasylyk C., Flores P., Gutman A., Wasylyk B. PEA3 is a nuclear target for transcription activation by non-nuclear oncogenes. EMBO J. 1989 Nov;8(11):3371–3378. doi: 10.1002/j.1460-2075.1989.tb08500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wasylyk C., Gutman A., Nicholson R., Wasylyk B. The c-Ets oncoprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoproteins. EMBO J. 1991 May;10(5):1127–1134. doi: 10.1002/j.1460-2075.1991.tb08053.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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