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. 2000 Feb 1;82(5):1041–1050. doi: 10.1054/bjoc.1999.1040

Increased activity of MAP, p70S6 and p90rs kinases is associated with AP-1 activation in spontaneous liver tumours, but not in adjacent tissue in mice

J Ostrowski 1, M Woszczynski 2, P Kowalczyk 1, T Wocial 1, E Hennig 1, L Trzeciak 1, P Janik 3, K Bomsztyk 4
PMCID: PMC2374428  PMID: 10737387

Abstract

Growth factor-responsive protein kinases regulate expression of genes involved in cell cycle control, cell proliferation and differentiation. To better understand the role of these kinases in the abnormal proliferation of malignant cells, we examined basal and epidermal growth factor (EGF)-inducible mitogen-activated protein kinase (MAPK), p70S6k and p90rsk activities in spontaneous hepatocellular neoplasms (adenomas and carcinomas) from CBA-T6 mice and in L1 sarcoma tumours implanted in livers of BALB/c mice. In spontaneous and implanted hepatic tumours, basal cytoplasmic and nuclear MAPK, p70S6k and p90rsk activities were significantly higher compared to the activities found in the part of the liver uninvolved by the tumour. Interestingly, the activities of these enzymes in the uninvolved tissue of the livers harbouring the tumour were higher compared to the livers from control mice. Basal kinase activities correlated with tumour morphology; they were lower in adenomas than in carcinomas and sarcomas. In contrast to basal activities, EGF-triggered kinase responses in normal livers and hepatic tumours were indistinguishable. Activating protein-1 (AP-1) DNA-binding activity was detected in tumours but not in the adjacent tissues. Constitutively activated kinases and AP-1 transcription factor found in hepatic malignancies are reminiscent of cells activated by EGF, suggesting that EGF and its intracellular effectors play a role in these malignancies. © 2000 Cancer Research Campaign

Keywords: MAPK, p706Sk, p90rsk, AP-1, ODC, EGF, liver neoplasms

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Selected References

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  1. Banerjee P., Ahmad M. F., Grove J. R., Kozlosky C., Price D. J., Avruch J. Molecular structure of a major insulin/mitogen-activated 70-kDa S6 protein kinase. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8550–8554. doi: 10.1073/pnas.87.21.8550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boulikas T. Phosphorylation of transcription factors and control of the cell cycle. Crit Rev Eukaryot Gene Expr. 1995;5(1):1–77. [PubMed] [Google Scholar]
  3. Carpenter G., Cohen S. Epidermal growth factor. J Biol Chem. 1990 May 15;265(14):7709–7712. [PubMed] [Google Scholar]
  4. Decker S. Phosphorylation of ribosomal protein S6 in avian sarcoma virus-transformed chicken embryo fibroblasts. Proc Natl Acad Sci U S A. 1981 Jul;78(7):4112–4115. doi: 10.1073/pnas.78.7.4112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Downward J. Lipid-regulated kinases: some common themes at last. Science. 1998 Jan 30;279(5351):673–674. doi: 10.1126/science.279.5351.673. [DOI] [PubMed] [Google Scholar]
  7. Fausto N., Laird A. D., Webber E. M. Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration. FASEB J. 1995 Dec;9(15):1527–1536. doi: 10.1096/fasebj.9.15.8529831. [DOI] [PubMed] [Google Scholar]
  8. Frith C. H., Ward J. M., Turusov V. S. Tumours of the liver. IARC Sci Publ. 1994;(111):223–269. [PubMed] [Google Scholar]
  9. Huber B. E., Heilman C. A., Thorgeirsson S. S. Poly(A+)RNA levels of growth-, differentiation- and transformation-associated genes in the progressive development of hepatocellular carcinoma in the rat. Hepatology. 1989 May;9(5):756–762. doi: 10.1002/hep.1840090517. [DOI] [PubMed] [Google Scholar]
  10. Janik P., Bertram J. S., Szaniawska B. Modulation of lung tumor colony formation by a subcutaneously growing tumor. J Natl Cancer Inst. 1981 Jun;66(6):1155–1158. doi: 10.1093/jnci/66.6.1155. [DOI] [PubMed] [Google Scholar]
  11. Kozma S. C., Ferrari S., Bassand P., Siegmann M., Totty N., Thomas G. Cloning of the mitogen-activated S6 kinase from rat liver reveals an enzyme of the second messenger subfamily. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7365–7369. doi: 10.1073/pnas.87.19.7365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lee W., Haslinger A., Karin M., Tjian R. Activation of transcription by two factors that bind promoter and enhancer sequences of the human metallothionein gene and SV40. Nature. 1987 Jan 22;325(6102):368–372. doi: 10.1038/325368a0. [DOI] [PubMed] [Google Scholar]
  13. Levitzki A. Targeting signal transduction for disease therapy. Curr Opin Cell Biol. 1996 Apr;8(2):239–244. doi: 10.1016/s0955-0674(96)80071-8. [DOI] [PubMed] [Google Scholar]
  14. Lewis T. S., Shapiro P. S., Ahn N. G. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998;74:49–139. doi: 10.1016/s0065-230x(08)60765-4. [DOI] [PubMed] [Google Scholar]
  15. Licato L. L., Keku T. O., Wurzelmann J. I., Murray S. C., Woosley J. T., Sandler R. S., Brenner D. A. In vivo activation of mitogen-activated protein kinases in rat intestinal neoplasia. Gastroenterology. 1997 Nov;113(5):1589–1598. doi: 10.1053/gast.1997.v113.pm9352861. [DOI] [PubMed] [Google Scholar]
  16. Magi-Galluzzi C., Mishra R., Fiorentino M., Montironi R., Yao H., Capodieci P., Wishnow K., Kaplan I., Stork P. J., Loda M. Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. Lab Invest. 1997 Jan;76(1):37–51. [PubMed] [Google Scholar]
  17. Marshall C. J. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev. 1994 Feb;4(1):82–89. doi: 10.1016/0959-437x(94)90095-7. [DOI] [PubMed] [Google Scholar]
  18. McGowan J. A., Strain A. J., Bucher N. L. DNA synthesis in primary cultures of adult rat hepatocytes in a defined medium: effects of epidermal growth factor, insulin, glucagon, and cyclic-AMP. J Cell Physiol. 1981 Sep;108(3):353–363. doi: 10.1002/jcp.1041080309. [DOI] [PubMed] [Google Scholar]
  19. Moller D. E., Xia C. H., Tang W., Zhu A. X., Jakubowski M. Human rsk isoforms: cloning and characterization of tissue-specific expression. Am J Physiol. 1994 Feb;266(2 Pt 1):C351–C359. doi: 10.1152/ajpcell.1994.266.2.C351. [DOI] [PubMed] [Google Scholar]
  20. Mullhaupt B., Feren A., Fodor E., Jones A. Liver expression of epidermal growth factor RNA. Rapid increases in immediate-early phase of liver regeneration. J Biol Chem. 1994 Aug 5;269(31):19667–19670. [PubMed] [Google Scholar]
  21. Nadori F., Lardeux B., Rahmani M., Bringuier A., Durand-Schneider A. M., Bernuau D. Presence of distinct AP-1 dimers in normal and transformed rat hepatocytes under basal conditions and after epidermal growth factor stimulation. Hepatology. 1997 Dec;26(6):1477–1483. doi: 10.1002/hep.510260614. [DOI] [PubMed] [Google Scholar]
  22. Oka H., Chatani Y., Hoshino R., Ogawa O., Kakehi Y., Terachi T., Okada Y., Kawaichi M., Kohno M., Yoshida O. Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res. 1995 Sep 15;55(18):4182–4187. [PubMed] [Google Scholar]
  23. Ostrowski J., Sims J. E., Sibley C. H., Valentine M. A., Dower S. K., Meier K. E., Bomsztyk K. A serine/threonine kinase activity is closely associated with a 65-kDa phosphoprotein specifically recognized by the kappa B enhancer element. J Biol Chem. 1991 Jul 5;266(19):12722–12733. [PubMed] [Google Scholar]
  24. Ostrowski J., Trzeciak L., Kołodziejski J., Bomsztyk K. Increased constitutive activity of mitogen-activated protein kinase and renaturable 85 kDa kinase in human-colorectal cancer. Br J Cancer. 1998 Nov;78(10):1301–1306. doi: 10.1038/bjc.1998.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ostrowski J., Wojciechowski K., Konturek S. J., Butruk E. Inhibitory effect of EGF on secretory response of rat parietal cells is associated with an induction of ODC. Am J Physiol. 1993 Jun;264(6 Pt 1):C1428–C1433. doi: 10.1152/ajpcell.1993.264.6.C1428. [DOI] [PubMed] [Google Scholar]
  26. Pegg A. E. Recent advances in the biochemistry of polyamines in eukaryotes. Biochem J. 1986 Mar 1;234(2):249–262. doi: 10.1042/bj2340249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pullen N., Thomas G. The modular phosphorylation and activation of p70s6k. FEBS Lett. 1997 Jun 23;410(1):78–82. doi: 10.1016/s0014-5793(97)00323-2. [DOI] [PubMed] [Google Scholar]
  28. Santos E., Martin-Zanca D., Reddy E. P., Pierotti M. A., Della Porta G., Barbacid M. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science. 1984 Feb 17;223(4637):661–664. doi: 10.1126/science.6695174. [DOI] [PubMed] [Google Scholar]
  29. Sturgill T. W., Wu J. Recent progress in characterization of protein kinase cascades for phosphorylation of ribosomal protein S6. Biochim Biophys Acta. 1991 May 17;1092(3):350–357. doi: 10.1016/s0167-4889(97)90012-4. [DOI] [PubMed] [Google Scholar]
  30. Tamori A., Nishiguchi S., Kuroki T., Seki S., Kobayashi K., Kinoshita H., Otani S. Relationship of ornithine decarboxylase activity and histological findings in human hepatocellular carcinoma. Hepatology. 1994 Nov;20(5):1179–1186. [PubMed] [Google Scholar]
  31. Thomas G., Siegmann M., Gordon J. Multiple phosphorylation of ribosomal protein S6 during transition of quiescent 3T3 cells into early G1, and cellular compartmentalization of the phosphate donor. Proc Natl Acad Sci U S A. 1979 Aug;76(8):3952–3956. doi: 10.1073/pnas.76.8.3952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Towatari M., Iida H., Tanimoto M., Iwata H., Hamaguchi M., Saito H. Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells. Leukemia. 1997 Apr;11(4):479–484. doi: 10.1038/sj.leu.2400617. [DOI] [PubMed] [Google Scholar]
  33. Westwick J. K., Fleckenstein J., Yin M., Yang S. Q., Bradham C. A., Brenner D. A., Diehl A. M. Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo. Am J Physiol. 1996 Nov;271(5 Pt 1):G780–G790. doi: 10.1152/ajpgi.1996.271.5.G780. [DOI] [PubMed] [Google Scholar]
  34. Williams-Ashman H. G., Coppoc G. L., Weber G. Imbalance in ornithine metabolism in hepatomas of different growth rates as expressed in formation of putrescine, spermidine, and spermine. Cancer Res. 1972 Sep;32(9):1924–1932. [PubMed] [Google Scholar]
  35. Yang E. B., Mack P., Cheng L. Y. Studies of epidermal growth factor (EGF) receptor in plasma membrane from rat liver and hepatoma tissues. Biochem Mol Biol Int. 1994 May;33(2):221–228. [PubMed] [Google Scholar]

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