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Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

Abstract

Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 melanoma cells. The present study demonstrates that this effect depends on the activation of STAT transcription factors. We observed a correlation between the extent of growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 receptor or oncostatin M (OSM) and the intensities of STAT3 and STAT1 signals. A truncated chimeric receptor retaining only the membrane-proximal region of gp130, the common signal transducer of IL-6-type cytokines, did neither activate STATs nor mediate growth arrest of stable transfectants. These functions were restored by the addition of short STAT recruitment modules comprising critical tyrosine residues from gp130 (Y767, Y814). A receptor carrying tyrosine module Y759 of gp130 effectively mediated activation of the phosphatase SHP-2 but did not alter cell growth. Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the inhibitory effect of OSM and IL-6 in A375 cells. In addition, we have identified the cyclin-dependent kinase inhibitor p27/Kip1 as a novel target to be regulated by IL-6-type cytokines. Stimulation-dependent upregulation of p27 mRNA occurred STAT3-dependently. Also p27 protein accumulated which coincided with the disappearance of hyperphosphorylated retinoblastoma protein in three human melanoma cell lines sensitive to IL-6-type cytokines.

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References

  • Arcone R, Pucci P, Zappacosta F, Fontaine V, Malorni A, Marino G and Ciliberto G. . 1991 Eur. J. Biochem. 198: 541–547.

  • Bellido T, O'Brien CA, Roberson PK and Manolagas SC. . 1998 J. Biol. Chem. 273: 21137–21144.

  • Boeuf H, Hauss C, De Graeve F, Baran N and Kedinger C. . 1997 J. Cell. Biol. 138: 1207–1217.

  • Boulton TG, Stahl N and Yancopoulos GD. . 1994 J. Biol. Chem. 269: 11648–11655.

  • Casagrande F, Bacqueville D, Pillaire MJ, Malecaze F, Manenti S, Breton-Douillon M and Darbon JM. . 1998 FEBS Lett. 422: 385–390.

  • Chen L, Mory Y, Zilberstein A and Revel M. . 1988 Proc. Natl. Acad. Sci. USA 85: 8037–8041.

  • Dittrich E, Renfrew Haft C, Muys L, Heinrich PC and Graeve L. . 1996 J. Biol. Chem. 271: 5487–5494.

  • Douglas AM, Goss GA, Sutherland RL, Hilton DJ, Berndt MC, Nicola NA and Begley CG. . 1997 Oncogene 14: 661–669.

  • Ernst M, Gearing DP and Dunn AR. . 1994 EMBO J. 13: 1574–1584.

  • Florenes VA, Maelandsmo GM, Kerbel RS, Slingerland JM, Nesland JM and Holm R. . 1998 Am. J. Pathol. 153: 305–312.

  • Frangioni JV and Neel BG. . 1993 Anal. Biochem. 210: 179–187.

  • Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K and Hirano T. . 1996 Immunity 5: 449–460.

  • Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K, Hibi M and Hirano T. . 1998 EMBO J. 17: 6670–6677.

  • Ganapathi MK, Weizer AK, Borsellino S, Bukowski RM, Ganapathi R, Rice T, Casey G and Kawamura K. . 1996 Cell Growth Differ. 7: 923–929.

  • Gearing DP, Comeau MR, Friend DJ, Gimpel SD, Thut CJ, McGourty J, Brasher KK, King JA, Gillis S, Mosley B, Ziegler SF and Cosman D. . 1992 Science 255: 1434–1437.

  • Gerhartz C, Heesel B, Sasse J, Hemmann U, Landgraf C, Schneider-Mergener J, Horn F, Heinrich PC and Graeve L. . 1996 J. Biol. Chem. 271: 12991–12998.

  • Heinrich PC, Behrmann I, Müller-Newen G, Schaper F and Graeve L. . 1998 Biochem. J. 334: 297–314.

  • Herlyn M. . 1990 Cancer and Metastasis Rev. 9: 101–112.

  • Hirano T. . 1998 Int. Rev. Immunol. 16: 249–284.

  • Horn D, Fitzpatrick WC, Gompper PT, Ochs V, Bolton-Hansen M, Zarling J, Malik N, Todaro GJ and Linsley PS. . 1990 Growth Factors 2: 157–165.

  • Ihara S, Nakajima K, Fukada T, Hibi M, Nagata S, Hirano T and Fukui Y. . 1997 EMBO J. 16: 5345–5352.

  • Kim H, Hawley TS, Hawley RG and Baumann H. . 1998 Mol. Cell. Biol. 18: 1525–1533.

  • Kumar G, Gupta S, Wang S and Nel, AE. . 1994 J. Immunol. 153: 4436–4447.

  • Lee IS, Liu Y, Narazaki M, Hibi M, Kishimoto T and Taga T. . 1997 FEBS Lett. 401: 133–137.

  • Lu C, Vickers MF and Kerbel RS. . 1992 Proc. Natl. Acad. Sci. USA 89: 9215–9219.

  • Lu C, Rak JW, Kobayashi H and Kerbel RS. . 1993 Cancer Res. 53: 2708–2711.

  • Lu C, Sheehan C, Rak JW, Chambers CA, Hozumi N and Kerbel RS. . 1996 Clin. Cancer Res. 2: 1417–1425.

  • Mackiewicz A, Schooltink H, Heinrich PC and Rose-John S. . 1992 J. Immunol. 149: 2021–2027.

  • Manenti S, Malecaze F, Chap H and Darbon JM. . 1998 Cancer Res. 58: 1429–1434.

  • Matsuda T, Fukada T, Takahashi-Tezuka M, Okuyama Y, Fujitani Y, Hanazono Y, Hirai H and Hirano T. . 1995a J. Biol. Chem. 270: 11037–11039.

  • Matsuda T, Takahashi-Tezuka M, Fukada T, Okuyama Y, Fujitani Y, Tsukada S, Mano H, Hirai H, Witte ON and Hirano T. . 1995b Blood 85: 627–633.

  • May P, Gerhartz C, Heesel B, Welte T, Doppler W, Graeve L, Horn F and Heinrich PC. . 1996 FEBS. Lett. 394: 221–226.

  • Minami M, Inoue M, Wei S, Takeda K, Matsumoto M, Kishimoto T and Akira S. . 1996 Proc. Natl. Acad. Sci. USA 93: 3963–3966.

  • Morinaga Y, Suzuki H, Takatsuki F, Akiyama Y, Taniyama T, Matsushima K and Onozaki K. . 1989 J. Immunol. 143: 3538–3542.

  • Morse L, Chen D, Franklin D, Xiong Y and Chen-Kiang S. . 1997 Immunity 6: 47–56.

  • Mosley B, De Imus C, Friend D, Boiani N, Thoma B, Park LS and Cosman D. . 1996 J. Biol. Chem. 271: 32635–32643.

  • Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi M, Taga T and Kishimoto T. . 1991 Proc. Natl. Acad. Sci. USA 88: 11349–11353.

  • Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, Kitaoka T, Fukada T, Hibi M and Hirano T. . 1996 EMBO J. 15: 3651–3658.

  • Narimatsu M, Nakajima K, Ichiba M and Hirano T. . 1997 Biochem. Biophys. Res. Commun. 238: 764–768.

  • Niwa H, Burdon T, Chambers I and Smith A. . 1998 Genes Dev. 12: 2048–2060.

  • Oh J-W, Katz A, Harroch S, Eisenbach L, Revel M and Chebath J. . 1997 Oncogene 15: 569–577.

  • Schaper F, Gendo C, Eck M, Schmitz J, Grimm C, Anhuf D, Kerr IM and Heinrich PC. . 1998 Biochem. J. 335: 557–565.

  • Sherr CJ and Roberts JM. . 1995 Genes Dev. 9: 1149–1163.

  • Sporeno E, Barbato G, Graziani R, Pucci P, Nitti G and Paonessa G. . 1994 Cytokine 6: 255–264.

  • Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell Jr JE and Yancopoulos GD. . 1995 Science 267: 1349–1353.

  • Swope VB, Abdel-Malek Z, Kassem LM and Nordlund JJ. . 1991 J. Invest. Dermatol. 96: 180–185.

  • Symes A, Stahl N, Reeves SA, Farruggella T, Servidei T, Gearan T, Yancopoulos G and Fink JS. . 1997 Curr. Biol. 7: 697–700.

  • Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T and Kishimoto T. . 1989 Cell 58: 573–581.

  • Takizawa H, Ohtoshi T, Ohta K, Yamashita N, Hirohata S, Hirai K, Hiramatsu K and Ito K. . 1993 Cancer Res. 53: 4175–4181.

  • Thiel S, Behrmann I, Dittrich E, Muys L, Tavernier J, Wijdenes J, Heinrich PC and Graeve L. . 1998 Biochem. J. 330: 47–54.

  • Wegenka UM, Buschmann J, Lütticken C, Heinrich PC and Horn F. . 1993 Mol. Cell. Biol. 13: 276–288.

  • Weiergräber O, Hemmann U, Küster A, Müller-Newen G, Schneider J, Rose-John S, Kurschat P, Brakenhoff JP, Hart MH, Stabel S and Heinrich PC. . 1995 Eur. J. Biochem. 234: 661–669.

  • Wong LH, Krauer KG, Hatzinisiriou I, Estcourt MJ, Hersey P, Tam ND, Edmondson S, Devenish RJ and Ralph SJ. . 1997 J. Biol. Chem. 272: 28779–28785.

  • Yamanaka Y, Nakajima K, Fukada T, Hibi M and Hirano T. . 1996 EMBO J. 15: 1557–1565.

  • Zarling JM, Shoyab M, Marquardt H, Hanson MB, Lioubin MN and Todaro GJ. . 1986 Proc. Natl. Acad. Sci. USA 83: 9739–9743.

  • Zhong Z, Wen Z and Darnell Jr JE. . 1994 Science 264: 95–98.

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Acknowledgements

We thank Claudia Gerhartz and Birgit Heesel for providing receptor constructs, Hildegard Schmitz-Van de Leur for excellent technical assistance, Susanne Esser for preparation of the GST fusion protein, Lutz Graeve, Gerhard Müller-Newen and Fred Schaper for critical reading of the manuscript. We are grateful to Gennaro Ciliberto for providing OSM and to Dirk Eick for providing human p27 cDNA. Human recombinant erythropoietin was a generous gift of Boehringer Mannheim, Penzberg, Germany. This work was supported by the Volkswagen-Stiftung, the State Committee for Scientific Research (Warsaw), the Deutsche Forschungsgemeinschaft (Bonn), and by Fonds der Chemischen Industrie (Frankfurt).

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Kortylewski, M., Heinrich, P., Mackiewicz, A. et al. Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1. Oncogene 18, 3742–3753 (1999). https://doi.org/10.1038/sj.onc.1202708

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