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:

Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1

Oncogene volume 21, pages 1000–1008 (2002)Cite this article

Abstract

Members of the mitogen-activated protein kinase (MAPK) superfamily, including p38 kinase and SAPK/JNK, play a central role in mediating cellular response to environmental stress, growth factors and cytokines. Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine capable of eliciting mitogenic, motogenic and morphogenetic activities in responsive cells, and has been implicated in tumor development and metastasis. Binding of HGF/SF to its tyrosine kinase receptor c-Met stimulates multiple signal transduction pathways, leading to the activation of numerous transcription factors. We here report that HGF/SF can induce cyclin D1 expression in mouse melanoma cells, and that this up-regulation is mediated in part by the activating transcription factor-2 (ATF-2). HGF/SF-mediated phosphorylation of ATF-2 was reduced in the presence of either the p38 kinase-specific inhibitor SB203580, a dominant negative p38 mutant, the SAPK/JNK inhibitor JNK-interacting protein-1 (JIP-1), or the phosphatidylinositol 3-kinase (PI3K)-specific inhibitor LY294002. Activation of p38 kinase by HGF/SF was partially blocked by the PI3K-specific inhibitor as well. The upstream kinases for p38, MKK3/6, did not become activated following HGF/SF exposure, and ATF-2 activation was undiminished by transient transfection of a dominant negative MKK6 mutant. However, transcriptional up-regulation of cyclin D1 by HGF/SF was partially inhibited by the p38 kinase-specific inhibitor, and cyclin D1 protein induction was partially blocked by a dominant negative ATF-2 mutant. Notably, the p38 kinase-specific inhibitor was able to block melanoma cell proliferation but not motility. We conclude that the ATF-2 transcription factor becomes activated by HGF/SF through p38 MAPK and SAPK/JNK. Moreover, the p38-ATF-2 pathway can help mediate proliferation signals in tumor cells through transcriptional activation of key cell cycle regulators.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • 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

Similar content being viewed by others

References

  • Aaronson SA . 1991 Science 254: 1146–1153

    Article  CAS  Google Scholar 

  • Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG . 1995 J. Biol. Chem. 270: 23589–23597

    Article  CAS  Google Scholar 

  • Alberch JH, Hu MY, Cerra FB . 1995 Biochem. Biophys. Res. Commun. 209: 648–655

  • Allen RE, Sheehan SM, Taylor RG, Kendall TL, Rice GM . 1995 J. Cell Physiol. 165: 307–312

  • Awad MM, Enslen H, Boylan JM, Davis RJ, Gruppusso PA . 2000 J. Biol. Chem. 275: 38716–38721

    Article  CAS  Google Scholar 

  • Awasthi V, King RJ . 2000 Am. J. Physiol. Lung. Cell Mol. Physiol. 279: L942–L949

  • Bales ES, Dietrich C, Bandyopadhyay D, Schwahn DJ, Xu W, Didenko V, Leiss P, Conrad N, Pereira-Smith O, Orengo I, Medrano EE . 1999 J. Invest. Dermatol. 113: 1039–1046

  • Bennett AM, Tonks NK . 1997 Science 278: 405–408

  • Beviglia L, Kramer RH . 1999 Int. J. Cancer 83: 640–649

    Article  CAS  Google Scholar 

  • Chen F, Ding M, Lu Y, Leonard SS, Vallyathan V, Casttranova V, Shi X . 2000 J. Environ. Pathol. Toxicol. Oncol. 19: 231–238

  • Chen HC, Chan PC, Tang MJ, Cheng CH, Chang TJ . 1998 J. Biol. Chem. 273: 25777–25782

    Article  CAS  Google Scholar 

  • Chomczynski P, Sacchi N . 1987 Anal. Biochem. 162: 156–

  • Chuang SM, Liou GY, Yang JL . 2000 Carcinogenesis 21: 1491–1500

    Article  CAS  Google Scholar 

  • Coso OA, Chiariello M, Kalinec J, Kyriakis JM, Woodgett J, Gutkind JS . 1995 J. Biol. Chem. 270: 5620–5624

    Article  CAS  Google Scholar 

  • Coupland SE, Anastassio G, Stang A, Schilling H, Anagnostopoulos I, Bornfeld N, Stein H . 2000 J. Pathol. 191: 120–126

    Article  CAS  Google Scholar 

  • D’Amico M, Hulit J, Amanatullah DF, Zafonte BT, Albanese C, Bouzahzah B, Fu M, Augenlicht LH, Donehower LA, Takemaru K-I, Moon RT, Davis R, Lisanti M, Shtutma M, Zhurinsky J, Ben-Ze’ev A, Troussard AA, Dedhar S, Pestell RG . 2000 J. Biol. Chem. 275: 32649–32657

    Article  CAS  Google Scholar 

  • Dickens M, Rogers JS, Cavanagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL, Davis RJ . 1997 Science 277: 693–696

    Article  CAS  Google Scholar 

  • Ding M, Shi X, Dong Z, Chen F, Lu Y, Castranova V, Vallyathan V . 1999 J. Biol. Chem. 274: 30611–30616

    Article  CAS  Google Scholar 

  • Ferraccini R, Oivero M, Di Renzo MF, Martano M, De Giovani P, Nanni G, Basso G, Scotlandi K, Lollini PL, Comoglio PM . 1996 Oncogene 11: 1697–1705

  • Ferracini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, Cremona O, Campaccini M, Comoglio PM . 1995 Oncogene 10: 739–749

  • Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL, Conti CJ . 1994 Oncogene 9: 3627–3633

  • Gherardi E, Stoker M . 1991 Cancer Cell. 3: 227–232

  • Gillies RJ, Didier N, Denton M . 1986 Anal. Biochem. 159: 109–113

  • Hai T, Liu F, Coukos W, Green M . 1989 Genes Dev. 3: 2083–2090

  • Halaban R . 2000 Pigment Cell Res. 13: 4–14

    Article  CAS  Google Scholar 

  • Huang S, New L, Pan Z, Han J, Nemerow GR . 2000 J. Biol. Chem. 275: 12266–12272

    Article  CAS  Google Scholar 

  • Huguier S, Baguet J, Perez S, van Dam H, Castellazzi M . 1998 Mol. Cell. Biol. 18: 7020–7029

    Article  CAS  Google Scholar 

  • Hunter T, Pines J . 1994 Cell. 79: 573–582

    Article  CAS  Google Scholar 

  • Jeffers M, Rong S, Vande Woude GF . 1996 J. Mol. Med. 74: 505–513

  • Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida B, Zbar B, Vande Woude GF . 1997 Proc. Natl. Acad. Sci. 94: 11445–11450

  • Kim SJ, Wagner S, Liu F, O’Reilly MA, Robbins PD, Green MR . 1992 Nature 358: 331–334

    Article  CAS  Google Scholar 

  • Lai JF, Kao SC, Jiang ST, Tang MJ, Chan PC, Chen HC . 2000 J. Biol. Chem. 275: 7474–7480

    Article  CAS  Google Scholar 

  • Landshultz WH, Johnson PF, McKnight SL . 1988 Science 240: 1759–1764

    Article  CAS  Google Scholar 

  • Lee RJ, Albanese C, Stenger RJ, Watanabe G, Inghirami G, Haines III GK, Webster M, Muller WJ, Brugge JS, Davis RJ, Pestell RG . 1999 J. Biol. Chem. 274: 7341–7350

    Article  CAS  Google Scholar 

  • Macfarlane WM, Smith SB, James RFL, Clifton AD, Doza YN, Cohen P, Docherty K . 1997 J. Biol. Chem. 272: 20936–20944

    Article  CAS  Google Scholar 

  • Maekawa T, Sakura H, Kanei-Ishii C, Sudo T, Yoshimura T, Fujisawa J-I, Yoshida M, Ishii S . 1989 EMBO J. 8: 2023–2028

  • Matsumoto K, Nakamura T . 1996 J. Biochem. 119: 591–600

  • Musgrove EA, Hamilton JA, Lee CS, Sweeney KJ, Watts CK, Sutherland RL . 1993 Mol. Cell. Biol. 13: 3577–3587

    Article  CAS  Google Scholar 

  • Nakanishi K, Fujimoto J, Ukei T, Kishimoto K, Hashimoto-Tamaoki T, Furuyama J, Itho T, Sasaki Y, Okamoto E . 1999 Clin. Exp. Metastasis. 17: 507–514

  • Natali PG, Nicotra MR, Di Renzo MR, Prat M, Bigotti A, Cavalier R, Comoglio PM . 1993 Br. J. Cancer. 68: 746–750

  • Otshuka T, Takayama H, Sharp R, Celli G, LaRochelle WJ, Bottaro DP, Ellmore N, Vieiria W, Owens JW, Anver M, Merlino G . 1998 Cancer Res. 58: 5157–5167

  • Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS, Yoo NJ, Jang JJ, Pack S, Zhuang Z, Schmidt L, Zbar B, Lee LY . 1999 Cancer Res. 59: 307–310

  • Pedram A, Razandi M, Levin ER . 1998 J. Biol. Chem. 273: 26722–26728

    Article  CAS  Google Scholar 

  • Ponzetto C, Zhen Z, Audero E, Maina F, Bardelli A, Basile ML, Giordano S, Narismhan R, Comoglio PM . 1996 J. Biol. Chem. 271: 14119–14123

    Article  CAS  Google Scholar 

  • Raingeaud J, Whitmarsh AJ, Barret T, Derijard B, David RJ . 1996 Mol. Cell Biol. 16: 1247–1255

  • Read MA, Whitley MZ, Gupta S, Pierce JW, Best J, Davis RJ, Collins T . 1997 J. Biol. Chem. 272: 2753–2761

    Article  CAS  Google Scholar 

  • Rodrigues GA, Park M, Schelssinger J . 1997 EMBO J. 16: 2634–2645

  • Ronai Z, Yang Y-M, Fuchs SY, Adler V, Sardana M, Herlyn M . 1998 Oncogene 16: 523–531

    Article  CAS  Google Scholar 

  • Rosen EM, Lamszus K, Laterra J, Polverini PJ, Rubin S, Goldberg ID . 1997 J. Biol. Chem. 270: 27780–27787

  • Royal I, Lamarche-Vane N, Lamorte L, Kaibuchi K, Park M . 2000 Mol. Cell Biol. 11: 1709–1725

  • Rubin JS, Bottaro DP, Aaronson SA . 1993 Biochem. Biophys. Acta. 1155: 357–371

  • Saha D, Datta PK, Sheng H, Morrow JD, Wada M, Moses HL, Beauchamp RD . 1999 Neoplasia 1: 508–517

    Article  CAS  Google Scholar 

  • Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Sherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil M, Orcutt T, Stackhouse ML, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Strokel S, Lerman MI, Lineham WM, Zbar B . 1997 Nat. Genet. 16: 68–73

  • Shambaugh III GE, Lee RJ, Watanabe G, Erfurth F, Karnezis AN, Koch AE, Haines III GK, Halloran M, Brodie BA, Pestell RG . 1996 J. Neuropathol. Exp. Neurol. 55: 1010–1021

  • Sherr CJ . 1994 Cell. 79: 551–555

    Article  CAS  Google Scholar 

  • Shimizu M, Nomura Y, Suzuki H, Ichikawa E, Takeuchi A, Suzuki M, Nakamura T, Nakajima T, Oda K . 1998 Exp. Cell Res. 239: 93–103

  • Spector M, Nguyen VA, Sheng X, He L, Woodward J, Fan S, Baumgarten CM, Kunos G, Dent P, Gao B . 2000 Exp. Cell Res. 258: 109–120

  • Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM . 2000 Nature 405: 354–360

    Article  CAS  Google Scholar 

  • Tolnay E, Kuhren C, Wiethege T, Konig JE, Voss B, Muller KM . 1998 J. Cancer Res. Clin. Oncol. 124: 291–296

  • Tsai EY, Jain J, Pesavento PA, Rao A, Goldfeld AE . 1996 Mol. Cell. Biol. 16: 459–467

    Article  CAS  Google Scholar 

  • van Dam H, Duyndam M, Rottier R, Bosch A, de Vries-Smits L, Herrlich P, Zantema A, Angel P, van der Eb AJ . 1993 EMBO J. 12: 479–487

  • Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV . 1994 Nature 369: 669–671

    Article  CAS  Google Scholar 

  • Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W . 1996 Nature 384: 173–176

    Article  CAS  Google Scholar 

  • Weidner KM, Sachs M, Rietmacher D, Birchmeier W . 1995 Proc. Natl. Acad. Sci. 92: 2597–2601

  • Weimar IS, Voermans C, Bourhis JH, Miranda N, van der Berk PC, Nakamura T, de Gast GC, Gerristen WR . 1998 Leukemia 12: 195–1203

  • Yamashita J, Ogawa M, Yamashita S, Nomura K, Kuramoto M, Saishoji T, Shin S . 1994 Cancer Res. 54: 1630–1633

  • Yao Y, Jin L, Fuchs A, Joseph A, Hastings H, Goldberg ID, Rosen EM . 1996 Am. J. Pathol. 149: 1707–1717

  • Zarnegar R, Michalopoulos GK . 1995 J. Cell Biol. 129: 1177–1180

  • Zhuang Z, Park WS, Packk S, Schmidt L, Vortmeyer E, Park E, Pham T, Weil RJ, Candidus S, Lubensky IA, Lineham B, Zbar B, Weirich G . 1998 Nat. Genet. 20: 66–69

  • Zohn IE, Symons M, Chrzanowska-Wodnicka M, Westwick JK, Der CJ . 1998 Mol. Cell. Biol. 18: 1225–1235

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, 20892-4264, Maryland, MD, USA

    Juan A Recio & Glenn Merlino

Authors
  1. Juan A Recio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Glenn Merlino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Glenn Merlino.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Recio, J., Merlino, G. Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. Oncogene 21, 1000–1008 (2002). https://doi.org/10.1038/sj.onc.1205150

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205150

Keywords

Search

Advanced search

Quick links