Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma

Oncogene volume 18, pages 1023–1032 (1999)Cite this article

Abstract

Human melanoma cell lines derived from early stage primary tumors are particularly sensitive to growth arrest induced by interleukin-6 (IL-6). This response is lost in cell lines derived from advanced lesions, a phenomenon which may contribute to tumor aggressiveness. We sought to determine whether resistance to growth inhibition by IL-6 can be explained by oncogenic alterations in cell cycle regulators or relevant components of intracellular signaling. Our results show that IL-6 treatment of early stage melanoma cell lines caused G1 arrest, which could not be explained by changes in levels of G1 cyclins (D1, E), cdks (cdk4, cdk2) or by loss of cyclin/cdk complex formation. Instead, IL-6 caused a marked induction of the cdk inhibitor p21WAF1/CIP1 in three different IL-6 sensitive cell lines, two of which also showed a marked accumulation of the cdk inhibitor p27Kip1. In contrast, IL-6 failed to induce p21WAF1/CIP1 transcript and did not increase p21WAF1/CIP1 or p27Kip1 proteins in any of the resistant lines. In fact, of five IL-6 resistant cell lines, only two expressed detectable levels of p21WAF1/CIP1 mRNA and protein, while in three other lines, p21WAF1/CIP1 was undetectable. IL-6 dependent upregulation of p21WAF1/CIP1 was associated with binding of both STAT3 and STAT1 to the p21WAF1/CIP1 promoter. Surprisingly, however, IL-6 stimulated STAT binding to this promoter in both sensitive and resistant cell lines (with one exception), suggesting that gross deregulation of this event is not the unifying cause of the defect in p21WAF1/CIP1 induction in IL-6 resistant cells. In somatic cell hybrids of IL-6 sensitive and resistant cell lines, the resistant phenotype was dominant and IL-6 failed to induce p21WAF1/CIP1. Thus, our results suggest that in early stage human melanoma cells, IL-6 induced growth inhibition involves induction of p21WAF1/CIP1 which is lost in the course of tumor progression presumably as a result of a dominant oncogenic event.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Andrews NC and Faller DV. . 1991 Nucleic Acids. Res. 19: 2499.

  • Barnhill RL and Levy MA. . 1993 Am. J. Pathol. 143: 99–104.

  • Borsellino N, Belldegrum A and Bonavida B. . 1995 Cancer Res. 55: 4633–4639.

  • Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ and Kern SE. . 1994 Nat. Genet. 8: 27–32.

  • Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, Franssen E, Pritchard KI and Slingerland JM. . 1997 Nat. Med. 3: 227–230.

  • Chin YE, Kitagawa M, Su W-CS, You Z-H, Iwamoto Y and Fuk X-Y. . 1996 Science 272: 719–722.

  • Chiu JJ, Sgagias MK and Cowan KH. . 1996 Clin. Cancer Res. 2: 215–221.

  • Church GM and Gilbert W. . 1984 Proc. Natl. Acad. Sci. USA 81: 1991–1995.

  • Cornil I, Theodorescu D, Man S, Herlyn M, Jambrosic J and Kerbel RS. . 1991 Proc. Natl. Acad. Sci. USA 88: 6028–6032.

  • Di Leonardo A, Linke SP, Clarkin K and Wahl GM. . 1994 Genes Dev. 8: 2540–2551.

  • Dulic V, Lees E and Reed SI. . 1992 Science 257: 1958–1961.

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 Cell 75: 817–825.

  • Eustace D, Han X, Gooding R, Rowbottom A, Riches P and Heyderman E. . 1993 Gyne. Oncol. 50: 15–19.

  • Flørenes VA, Bhattacharya N, Bani MR, Ben-David Y, Kerbel RS and Slingerland JM. . 1996 Oncogene 13: 2447–2457.

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

  • Flores JF, Walker GJ, Glendening JM, Haluska FG, Castresana JS, Rubio M-P, Pastorfide GC, Boyer LA, Kao WH, Bulyk ML, Barnhill RL, Hayward NK, Housman DE and Fountain JW. . 1996 Cancer Res. 56: 5023–5032.

  • Fynan TM andReiss M. . 1993 Crit. Rev. Oncog. 4: 493–540.

  • Hannon GJ and Beach D. . 1994 Nature 371: 257–261.

  • Hengst L and Reed SI. . 1996 Science 271: 1861–1864.

  • Hirama T and Koeffler HP. . 1995 Blood 86: 841–854.

  • Ishikawa M, Dennis JW, Man S and Kerbel RS. . 1988a Cancer Res. 48: 665–670.

  • Ishikawa M, Fernandez B and Kerbel RS. . 1988b Cancer Res. 48: 4897–4903.

  • Jennings MT, Maciunas RJ, Carver R, Bascome CC, Juneau P, Misulis K and Moses HL. . 1991 Int. J. Cancer 49: 129–139.

  • Jiang H, Lin J, Su Z, Herlyn M, Kerbel RS, Weissman BE, Welch DR and Fisher PB. . 1995 Oncogene 10: 1855–1864.

  • Jiang H, Lin J, Su ZZ, Collart FR, Huberman and Fisher PB. . 1994 Oncogene 9: 3397–3406.

  • Kamb A, Gruis NA, Weaver-feldhaus J, Liu Q, Harshman K, Tavtigan SV, Stockert E, Day III RS, Johnson BE and Skolnick MH. . 1994a Science 264: 436–440.

  • Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y and Weaver-feldhaus J. . 1994b Nat. Genet. 8: 23–26.

  • Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaku H, Tang B, Tanabe O, Tanada H, Kuramoto A and Kishimoto T. . 1988 Nature 332: 83–85.

  • Kishimoto T. . 1989 Blood 74: 1–10.

  • Kishimoto T, Akira S, Narazaki M and Taga T. . 1995 Blood 86: 1243–1254.

  • Koff A, Masahiko O, Polyak K, Roberts JM and Massague J. . 1993 Science 260: 536–539.

  • Laiho M, Weis FMB and Massague J. . 1990 J. Biol. Chem. 265: 18518–18524.

  • Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM and Pagano M. . 1997 Nat. Med. 3: 231–234.

  • Lu C and Kerbel RS. . 1993 J. Cell Biol. 120: 1281–1288.

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

  • MacDougall JR, Kobayashi H and Kerbel RS. . 1993 Mol. Cell. Different. 1: 21–40.

  • MacDougall JR, Lin Y, Rak J and Kerbel RS. . 1995 Cancer Res. 55/18: 4174–4181.

  • Maelandsmo GM, Flørenes VA, Hovig E, Oyjord T, Engebraaten O, Holm R, Borresten A-L and Fodstad O. . 1996 Br. J. Cancer 73: 909–916.

  • Maelandsmo GM, Holm R, Fodstad O, Kerbel RS and Flørenes VA. . 1996 Am. J. Pathol. 149: 1813–1822.

  • Martin-Castellanos C and Moreno S. . 1997 Trends in Cell Biol. 7: 95–98.

  • Matsumura I, Ishikawa J, Nakajima K, Oritani K, Tomiyama Y, Miyagawa J, Kato T, Miyazaki H, Matsuzawa Y and Kanakura Y. . 1997 Mol. Cell Biol. 17: 2933–2943.

  • Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ and Kato JY. . 1994 Mol. Cell Biol. 14: 2066–2076.

  • Miki S, Iswano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, Sonoda T, Hirano T and Kishimoto T. . 1989 Febs. Lett. 250: 607–610.

  • Mitzutani Y, Bonavida B, Koishihara Y, Akamatsu K, Ohsugi Y and Yoshida O. . 1995 Cancer Res. 55: 590–596.

  • Morgan DO. . 1995 Nature 374: 131–134.

  • Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K and Carson DA. . 1994 Nature 368: 753–756.

  • Noda A, Ning Y, Venable SF, Pereira-Smith OM and Smith JR. . 1994 Exp. Cell Res. 211: 90–98.

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

  • Okamoto M, Lee C and Oyasu R. . 1997 Cancer Res. 57: 141–146.

  • Otsuki T, Clark HM, Wellmann A, Jaffe ES and Raffeld M. . 1995 Cancer Res. 55: 1436–1440.

  • Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF and Rolfe M. . 1995 Science 269: 682–685.

  • Parry D, Bates S, Mann DJ and Peters G. . 1995 EMBO J. 14: 503–511.

  • Polyak K, Kato J-Y, Solomon MJ, Sherr CJ, Massague J, Roberts JM and Koff A. . 1994a Genes & Develop. 8: 9–22.

  • Polyak K, Lee M-H, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P and Massague J. . 1994b Cell 78: 59–66.

  • Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, Daling JR and Roberts JM. . 1997 Nat. Med. 3: 222–225.

  • Rak J, Filmus J and Kerbel RS. . 1996 Eur. J. Cancer 32A: 2438–2450.

  • Reed JA, Loganzo F, Shea CR, Walker GJ, Fores JF, Glendening JM, Bogdany JK, Shiel MJ, Haluska FG, Fountain JW and Albino AP. . 1995 Cancer Res. 55: 2713–2718.

  • Resnitzky D, Tiefenbrun N, Berissi H and Kimchi A. . 1992 Proc. Natl. Acad. Sci. USA 89: 402–406.

  • Reynisdottir I, Polyak K, Iavarone A and Massague J. . 1995 Genes & Develop. 9: 1831–1845.

  • Sandhu C, Garbe J, Bhattacharya N, Daksis J, Pan CH, Yaswen P, Koh J, Slingerland JM and Stampfer MR. . 1997 Mol. Cell Biol. 17: 2458–2467.

  • Shao ZM, Dawson MI, Li XS, Rishi AK, Sheikh MS, Han QX, Ordonez JV, Shroot B and Fontana JA. . 1995 Oncogene 11: 493–504.

  • Sherr CJ. . 1996 Science 274: 1672–1677.

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

  • Shiohara M, El-Deiry WS, Wada M, Nakamaki T, Takeuchi S, Yang R, Chen D-L, Vogelstein B and Koeffler HP. . 1994 Blood 84: 3781–3784.

  • Slingerland JM, Hengst L, Pan C-H, Alexander D, Stampfer MR and Reed SI. . 1994 Mol. Cell. Biol. 14: 3683–3694.

  • Spruck CH, 3rd, Gonzalez-Zulueta M, Shibata A, Simoneau AR, Lin MF, Gonzales F, Tsai YC and Jones PA. . 1994 Nature 370: 183–184.

  • Steinman RA, Hoffman B, Iro A, Guillouf C, Liebermann DA and el-Houseini ME. . 1994 Oncogene 9: 3389–3396.

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

  • Tam SW, Theodoras AM, Shay JW, Draetta GF and Pagano M. . 1994 Oncogene 9: 2663–2674.

  • Vidal MJ, Loganzo F, de Oliverira AR, Hayward NK and Albino AP. . 1995 Melanoma Res. 5: 243–250.

  • Welch DR and Riber M. . 1996 Mol. Cell. Different. 4: 91–111.

  • Zeng YX and El-Deiry WS. . 1996 Oncogene 12: 1557–1564.

  • Zhang XG, Klein B and Bataille R. . 1989 Blood 74: 11–13.

Download references

Acknowledgements

We thank those who kindly provided antibodies for these studies and Meenhard Herlyn for the WM panel of human melanoma cell lines. YE Chin is gratefully acknowledged for helpful discussion regarding the DNA band shift assay. We are grateful to Cassandra Cheng, Mina Viscardi and Lynda Woodcock for their excellent secretarial assistance. VAF is supported by a postdoctoral fellowship from the Medical Research Council of Canada and by stipends from the Norwegian Research Council and Lillemor Grobstocks legacy. This work was supported by a grant from the National Institutes of Health USA, CA 41223 to RSK and the National Cancer Institute of Canada to JMS. RSK is a Terry Fox Research Scientist of the National Cancer Institute of Canada. JMS is supported by Cancer Care Ontario.

Author information

Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto and Division of Cancer Biology Research, Sunnybrook Health Science Centre, 2075 Bayview Avenue, S-218 Toronto, M4N 3M5, Ontario, Canada

    Vivi Ann Flørenes, Chao Lu, Nandita Bhattacharya, Janusz Rak, Capucine Sheehan, Joyce M Slingerland & Robert S Kerbel

  2. Division of Medical Oncology, Toronto-Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, S-218 Toronto, M4N 3M5, Ontario, Canada

    Joyce M Slingerland

Authors
  1. Vivi Ann Flørenes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chao Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nandita Bhattacharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Janusz Rak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Capucine Sheehan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joyce M Slingerland
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert S Kerbel
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Flørenes, V., Lu, C., Bhattacharya, N. et al. Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. Oncogene 18, 1023–1032 (1999). https://doi.org/10.1038/sj.onc.1202382

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202382

Keywords

This article is cited by

Search

Advanced search

Quick links