Abstract
CDC25 phosphatases activate cyclin‐dependent kinases by removing inhibitory phosphate groups on the molecules and positively regulate the cell cycle progression. The expression of CDC25A, B and C was examined in gastric carcinoma cell lines and gastric carcinoma tissues by northern blotting and immunohistochemistry. The gastric carcinoma cell lines expressed CDC25A, B and C mRNA at various levels. The expression levels of CDC25B were generally higher than those of CDC25A and C. Of the 40 gastric carcinomas, 70% of the tumors expressed CDC25B mRNA at higher levels than the corresponding normal mucosas, while 38% overexpressed CDC25A mRNA. The CDC25C expression was at very low or undetectable levels. No obvious correlation was detected between the expression of CDC25B and p53 gene mutations. Inununohistochemically, CDC25‐positive tumor cells were detected in 43 (78%) of 55 gastric carcinoma cases, of which 27 (49%) were strongly positive. Strong expression of CDC25B protein was associated with advanced stage and deep invasion. Furthermore, the incidence of strong expression was significantly higher in carcinomas with nodal metastasis than in those without metastasis. These findings suggest that Overexpression of CDC25B may favor development and progression and may be an indicator of malignant behavior of gastric carcinomas.
Keywords: Overexpression, CDC25B, Human gastric carcinoma
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REFERENCES
- 1. ) Sherr , C. J.Gl phase progression: cycling on cue . Cell , 79 , 515 – 555 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Hunter , T. and Pines , J.Cyclins and cancer II: cyclin D and CDK inhibitors come of age . Cell , 79 , 573 – 582 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Sherr , C. J.Mammalian Gl cyclins . Cell , 73 , 1059 – 1065 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 4. ) EI‐Deiry , W. S. , Tokino , T. , Velculescu , V. E. , Levy , D. B. , Persons , R. , Trent , J. M. , Lin , D. , Mercer , W. E. , Kinzler , K. W. and Vogelstein , B, WAF1, a potential mediator of p53 tumor suppression . Cell , 75 , 817 – 825 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Harper , T. W. , Adami , G. R. , Wei , N. , Keyomarsi , K. and Elledge , S. J.The p21 Cdk‐interacting protein Cipl is a potent inhibitor of Gl cyclin‐dependent kinases . Cell , 75 , 805 – 816 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Polyak , K. , Kato , J. Y. , Solomon , M. J. , Sherr , C. J. , Massague , J. , Roberts , J. M. and Koff , A.p27Kipl, a cyclin‐Cdk inhibitor, links transforming growth factor‐,β and contact inhibition to cell cycle arrest . Gene Dev. , 8 , 9 – 22 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Toyoshima , H. and Hunter , T.p27, a novel inhibitor of Gl cyclin‐Cdk protein kinase activity, is related to p2I . Cell , 78 , 67 – 74 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Kamb , A. , Gruis , N. A. , Weaver‐Feldhaus , J. , Liu , Q. , Harshman , K. , Tavtigian , S. V. , Stockert , E. , Day , R. S. , Johnson , B. E. and Skolnick , M. H.A cell cycle regulator potentially involved in genesis of many tumor types . Science , 264 , 436 – 440 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Hannon , G. J. and Beach , D.p15INK4B is a potent effector of TGF‐β‐induced cell cycle arrest . Nature , 371 , 257 – 261 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Nobori , T. , Miura , K. , Wu , D. J. , Lois , A. , Takabayashi , K. and Carson , D. A.Deletions of the cyclin‐dependent kinase‐4 inhibitor gene in multiple human cancers . Nature , 368 , 753 – 756 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Serrano , M. , Hannon , G. J. and Beach , D.A new regulatory motif in cell‐cycle control causing specific inhibition of cyclin D/CDK4 . Nature , 366 , 704 – 707 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Parker , L. L. , Atherton‐Fessler , S. , Lee , M. S. , Ogg , S. , Falk , J. L. , Swenson , K. I. and Piwnica‐Worms , H.Cyclin promotes the tyrosine phosphorylation of p34cdc2 in a wee 1+ dependent manner . EMBO J. , 10 , 1255 – 1263 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. ) Parker , L. L. , Atherton‐Fessler , S. and Piwnica‐Worms , H.p107weel is a dual‐specificity kinase that phosphorylates p34cdc2 on tyrosine 15 . Proc. Nail Acad. Sci. USA , 89 , 2917 – 2921 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. ) Featherstone , C. and Russell , P.Fission yeast p107weel mitotic inhibitor is a tyrosine/serine kinase . Nature , 349 , 808 – 811 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Dunphy , W. G. and Kumagai , A.The cdc25 protein contains an intrinsic phosphatase activity . Cell , 67 , 189 – 196 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Galaktionov , K. and Beach , D.Specific activation of cdc25 tyrosine phosphatases by B‐type cyclins: evidence for multiple roles of mitotic cyclins . Cell , 67 , 1181 – 1194 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Qautier , J. , Solomon , M , Booher , R. , Bazan , J. and Kirshner , M.Cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2 . Cell , 67 , 197 – 211 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Millar , J. B. , McGowan , C. H. , Lenaers , G. , Jones , R. and Russell , P.p80cdc25 mitotic inducer is the tyrosine phosphatase that activates p34cdc2 kinase in fission yeast . EMBO J. , 10 , 4301 – 4309 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. ) Strausfeld , U. , Labbe , J. C. , Fesquet , D. , Cavadore , J. C. , Picard , A. , Sadhu , K. , Russell , P. and Dorée , M.Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 protein . Nature , 351 , 242 – 245 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Sadhu , K. , Reed , S. I. , Richardson , H. and Russell , P.Human homolog of fission yeast cdc25 mitotic inducer is predominantly expressed in G2 . Proc. Natl, Acad. Sci. USA , 87 , 5139 – 5143 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. ) Millar , J. B. , Blevitt , J. , Gerace , L. , Sadhu , K. , Featherstone , C , and Russell , P.p55CDC25 is a nuclear protein required for the initiation of mitosis in human cells . Proc. Natl. Acad. Sci. USA , 88 , 10500 – 10504 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. ) Jinno , S. , Suto , K. , Nagata , A. , Igarashi , M. , Kanaoka , Y. , Nojima , H. and Okayama , H.Cdc25A is a novel phosphatase functioning early in the cell cycle . EMBO J. , 13 , 1549 – 1556 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. ) Sebastian , B. , Kakizuka , A. and Hunter , T.Cdc25M2 activation of cyclin‐dependent kinases by dephosphoryla‐tion of threonine‐14 and tyrosine‐15 . Proc. Natl. Acad. Sci. USA , 90 , 3521 – 3524 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. ) Honda , R. , Ohba , Y. , Nagata , A. , Okayama , H. and Yasuda , H.Dephosphorylation of human p34cdc2 kinase on both Thr‐14 andTyr‐15 by human cdc25B phosphatase . FEBS Lett. , 318 , 331 – 334 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 25. ) Galaktionov , K. , Lee , A. K. , Eckstein , J. , Draetta , G. , Meckler , J. , Loda , M. and Beach , D.CDC25 phosphatases as potentialhuman oncogenes . Science , 269 , 1575 – 1577 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 26. ) Ochiai , A. , Yasui , W. and Tahara , E.Growth‐promoting effect of gastrin on human gastric carcinoma cell line TMK‐1 . Jpn. J. Cancer Res. , 76 , 1064 – 1071 ( 1985. ). [PubMed] [Google Scholar]
- 27. ) Yanagihara , K. , Seyama , T. , Tsumuraya , M. , Kamada , N. and Yokoro , K.Establishment and characterization of human signet ring cell gastric carcinoma cell lines with amplification of the c‐myc ncogene . Cancer Res. , 51 , 381 – 386 ( 1991. ). [PubMed] [Google Scholar]
- 28. ) Anese Research Society for Gastric Cancer . “ Japanese Classificationof Gastric Carcinoma ,” 1st EnglishEd. ( 1995. ). Kanehara Co. , Tokyo . [Google Scholar]
- 29. ) Yasui , W. , Kuniyasu , H. , Akama , Y. , Kitahara , K. , Nagafuchi , A. , Ishihara , S. , Tsukita , S. and Tahara , E.Expression of E‐cadherin, α‐ and β‐catenins in human gastric carcinomas: correlation with histology and tumor progression . Oncol. Rep. , 2 , 111 – 117 ( 1995. ). [PubMed] [Google Scholar]
- 30. ) Nagata , A. , Igarashi , M. , Jinno , S. , Suto , K. and Okayama , H.An additional homolog of the fission yeast cdc25 + gene occurs in human and is highly expressed in some cancer cells . New Biol , 3 , 959 – 968 ( 1991. ). [PubMed] [Google Scholar]
- 31. ) Yasui , W. , Ayhan , A. , Kitadai , Y. , Nishimura , K. , Yokozaki , H. , Ito , H. and Tahara , E.Increased expression of p34cdc2 and its kinase activity in human gastric and colonic carcinomas . Int. J. Cancer , 53 , 36 – 41 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 32. ) Yasui , W. , Ji , Z.‐Q. , Kuniyasu , H. , Ayhan , A. , Yokozaki , H. , Ito , H. and Tahara , E.Expression of transforming growth factor alpha in human tissues: immunohistochemical study and Northern blot analysis . Virchows Arch. A [Pathol. Anat]. , 21 , 513 – 519 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 33. ) Mattar , R. , Yokozaki , H. , Yasui , W. , Ito , H. and Tahara , E.p53 gene mutations in gastric cancer cell lines . Life Sci. Adv. Oncol. , 11 , 7 – 12 ( 1992. ). [Google Scholar]
- 34. ) Ito , R. , Kitadai , Y. , Kyo , E. , Yokozaki , H. , Yasui , W. , Yamashita , U. , Nikai , H. and Tahara , E.Interleukin lα acts as an autocrine growth stimulator for human gastric carcinoma cells . Cancer Res. , 53 , 4102 – 4106 ( 1993. ). [PubMed] [Google Scholar]
- 35. ) Yoshida , K. , Takanashi , A. , Kyo , E. , Ito , M. , Ito , H. , Niimoto , M. , Hattori , T. and Tahara , E.Epidermal growth factor induces the expression of its receptor gene in human gastric carcinoma cell line TMK‐1 . Jpn. J. Cancer Res. , 80 , 743 – 746 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. ) Yokozaki , H. , Kuniyasu , H. , Kitadai , Y. , Nishimura , K. , Todo , H. , Ayhan , A. , Yasui , W. , Ito , H. and Tahara , E.p53 point mutations in primary human gastric carcinomas . J. Cancer Res. Clin. Oncol. , 119 , 67 – 70 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 37. ) Akama , Y. , Yasui , W. , Kuniyasu , H. , Yokozaki , H. , Akagi , M. , Tahara , H. , Ishikawa , T. and Tahara , E.Genetic status and expression of the cyclin‐dependent kinase inhibitors in human gastric carcinoma cell lines . Jpn. J. Cancer Res. , 87 , 824 – 830 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. ) Tahara , E. , Sumiyoshi , H. , Hata , J. , Yasui , W. , Taniyama , K. , Hayashi , T. , Nagae , S. and Sakamoto , S.Human epidermal growth factor in gastric carcinoma as a biologic marker of high malignancy . Jpn. J. Cancer Res. , 77 , 145 – 152 ( 1986. ). [PubMed] [Google Scholar]
- 39. ) Galaktionov , K. , Jessus , C. and Beach , D.Rafl interaction with cdc25 phosphatase ties mitogenic signal trans‐duction to cell cycle activation . Genes Dev. , 9 , 1046 – 1058 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 40. ) Galaktionov , K. , Chen , X. and Beach , D.Cdc25 cell‐cycle phosphatase as a target of c‐myc . Nature , 382 , 511 – 517 ( 1996. ). [DOI] [PubMed] [Google Scholar]