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. 1999 Dec;81(7):1116–1121. doi: 10.1038/sj.bjc.6690817

Differential regulation of MAP kinase cascade in human colorectal tumorigenesis

K-S Park 1,2, N-G Kim 3, J J Kim 3, H Kim 3, Y H Ahn 1,2, K-Y Choi 1,2
PMCID: PMC2374318  PMID: 10584870

Abstract

Hyper-activation of mitogen-activated protein kinase (MAPK) has recently been reported in several human cancers and activation of MAPK in those cancers may be associated with carcinogenesis through aberrant cell proliferation. To understand the roles of the MAPK pathway in colorectal tumorigenesis, we examined the status of extracellular signal-regulated protein kinases (ERK1/2) in 21 colorectal tumour specimens and compared it with that of paired normals. The specific MAPK activities were two- to tenfold lower in 71% (15 out of 21 cases) of colorectal tumours compared to those in paired normals. The individual MAPK kinase (MEK) correlated with MAPK activities (P = 0.006). Reduction of the MAPK and MEK activities in colorectal tumours was also observed in adenomas. These results suggested that down-regulation of the MAPK cascade may be caused by early genetic event(s) and that it may be related to the loss of normal growth control. Although MAPK activities were down-regulated both in adenomas and carcinomas, activities of the MAPKs in carcinomas were higher than those of paired adenomas. These results suggested that MAPK activities may be increased in the adenoma-to-carcinoma sequence and that it may play a role in the tumour progression. Observation of the differential regulation of MAPK activities in colorectal tumorigeneis suggested roles for the MAPK pathway in both positive and negative controls of cell growth. © 1999 Cancer Research Campaign

Keywords: colorectal cancer, extracellular signal regulated kinase, Ras, MEK, Raf-1

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Selected References

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

  1. Ahnen D. J., Feigl P., Quan G., Fenoglio-Preiser C., Lovato L. C., Bunn P. A., Jr, Stemmerman G., Wells J. D., Macdonald J. S., Meyskens F. L., Jr Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res. 1998 Mar 15;58(6):1149–1158. [PubMed] [Google Scholar]
  2. Alexander W. S., Adams J. M., Cory S. Oncogene cooperation in lymphocyte transformation: malignant conversion of E mu-myc transgenic pre-B cells in vitro is enhanced by v-H-ras or v-raf but not v-abl. Mol Cell Biol. 1989 Jan;9(1):67–73. doi: 10.1128/mcb.9.1.67-73.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Attar B. M., Atten M. J., Holian O. MAPK activity is down-regulated in human colon adenocarcinoma: correlation with PKC activity. Anticancer Res. 1996 Jan-Feb;16(1):395–399. [PubMed] [Google Scholar]
  4. Atten M. J., Attar B. M., Holian O. Decreased MAP kinase activity in human gastric adenocarcinoma. Biochem Biophys Res Commun. 1995 Jul 26;212(3):1001–1006. doi: 10.1006/bbrc.1995.2069. [DOI] [PubMed] [Google Scholar]
  5. Blenis J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5889–5892. doi: 10.1073/pnas.90.13.5889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bos J. L. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682–4689. [PubMed] [Google Scholar]
  7. Cobb M. H., Goldsmith E. J. How MAP kinases are regulated. J Biol Chem. 1995 Jun 23;270(25):14843–14846. doi: 10.1074/jbc.270.25.14843. [DOI] [PubMed] [Google Scholar]
  8. Dent P., Jelinek T., Morrison D. K., Weber M. J., Sturgill T. W. Reversal of Raf-1 activation by purified and membrane-associated protein phosphatases. Science. 1995 Jun 30;268(5219):1902–1906. doi: 10.1126/science.7604263. [DOI] [PubMed] [Google Scholar]
  9. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  10. Groom L. A., Sneddon A. A., Alessi D. R., Dowd S., Keyse S. M. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J. 1996 Jul 15;15(14):3621–3632. [PMC free article] [PubMed] [Google Scholar]
  11. Guillem J. G., O'Brian C. A., Fitzer C. J., Forde K. A., LoGerfo P., Treat M., Weinstein I. B. Altered levels of protein kinase C and Ca2+-dependent protein kinases in human colon carcinomas. Cancer Res. 1987 Apr 15;47(8):2036–2039. [PubMed] [Google Scholar]
  12. He T. C., Sparks A. B., Rago C., Hermeking H., Zawel L., da Costa L. T., Morin P. J., Vogelstein B., Kinzler K. W. Identification of c-MYC as a target of the APC pathway. Science. 1998 Sep 4;281(5382):1509–1512. doi: 10.1126/science.281.5382.1509. [DOI] [PubMed] [Google Scholar]
  13. Janes P. W., Daly R. J., deFazio A., Sutherland R. L. Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. Oncogene. 1994 Dec;9(12):3601–3608. [PubMed] [Google Scholar]
  14. Kinzler K. W., Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996 Oct 18;87(2):159–170. doi: 10.1016/s0092-8674(00)81333-1. [DOI] [PubMed] [Google Scholar]
  15. Kopp R., Noelke B., Sauter G., Schildberg F. W., Paumgartner G., Pfeiffer A. Altered protein kinase C activity in biopsies of human colonic adenomas and carcinomas. Cancer Res. 1991 Jan 1;51(1):205–210. [PubMed] [Google Scholar]
  16. Lange-Carter C. A., Pleiman C. M., Gardner A. M., Blumer K. J., Johnson G. L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science. 1993 Apr 16;260(5106):315–319. doi: 10.1126/science.8385802. [DOI] [PubMed] [Google Scholar]
  17. Magnuson N. S., Beck T., Vahidi H., Hahn H., Smola U., Rapp U. R. The Raf-1 serine/threonine protein kinase. Semin Cancer Biol. 1994 Aug;5(4):247–253. [PubMed] [Google Scholar]
  18. Marais R., Light Y., Mason C., Paterson H., Olson M. F., Marshall C. J. Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C. Science. 1998 Apr 3;280(5360):109–112. doi: 10.1126/science.280.5360.109. [DOI] [PubMed] [Google Scholar]
  19. Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  20. Marcu K. B., Bossone S. A., Patel A. J. myc function and regulation. Annu Rev Biochem. 1992;61:809–860. doi: 10.1146/annurev.bi.61.070192.004113. [DOI] [PubMed] [Google Scholar]
  21. Marshall C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. doi: 10.1016/0092-8674(95)90401-8. [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. Owen A. J., Pantazis P., Antoniades H. N. Simian sarcoma virus--transformed cells secrete a mitogen identical to platelet-derived growth factor. Science. 1984 Jul 6;225(4657):54–56. doi: 10.1126/science.6328659. [DOI] [PubMed] [Google Scholar]
  24. Pumiglia K. M., Decker S. J. Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):448–452. doi: 10.1073/pnas.94.2.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sewing A., Wiseman B., Lloyd A. C., Land H. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol. 1997 Sep;17(9):5588–5597. doi: 10.1128/mcb.17.9.5588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Simon B., Weinel R., Höhne M., Watz J., Schmidt J., Körtner G., Arnold R. Frequent alterations of the tumor suppressor genes p53 and DCC in human pancreatic carcinoma. Gastroenterology. 1994 Jun;106(6):1645–1651. doi: 10.1016/0016-5085(94)90422-7. [DOI] [PubMed] [Google Scholar]
  27. Sivaraman V. S., Wang H., Nuovo G. J., Malbon C. C. Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest. 1997 Apr 1;99(7):1478–1483. doi: 10.1172/JCI119309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  29. Spandidos D. A., Kerr I. B. Elevated expression of the human ras oncogene family in premalignant and malignant tumours of the colorectum. Br J Cancer. 1984 Jun;49(6):681–688. doi: 10.1038/bjc.1984.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stevenson M. A., Pollock S. S., Coleman C. N., Calderwood S. K. X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NIH-3T3 cells through the formation of reactive oxygen intermediates. Cancer Res. 1994 Jan 1;54(1):12–15. [PubMed] [Google Scholar]
  31. 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]
  32. Vogel U. S., Dixon R. A., Schaber M. D., Diehl R. E., Marshall M. S., Scolnick E. M., Sigal I. S., Gibbs J. B. Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature. 1988 Sep 1;335(6185):90–93. doi: 10.1038/335090a0. [DOI] [PubMed] [Google Scholar]
  33. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  34. Woods D., Parry D., Cherwinski H., Bosch E., Lees E., McMahon M. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol. 1997 Sep;17(9):5598–5611. doi: 10.1128/mcb.17.9.5598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yao B., Zhang Y., Delikat S., Mathias S., Basu S., Kolesnick R. Phosphorylation of Raf by ceramide-activated protein kinase. Nature. 1995 Nov 16;378(6554):307–310. doi: 10.1038/378307a0. [DOI] [PubMed] [Google Scholar]
  36. Zheng C. F., Guan K. L. Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J Biol Chem. 1993 May 25;268(15):11435–11439. [PubMed] [Google Scholar]

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