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:

NDF/heregulin-induced cell cycle changes and apoptosis in breast tumour cells: role of PI3 kinase and p38 MAP kinase pathways

Oncogene volume 18, pages 3440–3451 (1999)Cite this article

Abstract

Neu differentiation factor (NDF)/heregulin activates ErbB2 via heterodimerization with the NDF receptors ErbB3 and ErbB4. Cells which express normal levels of these receptors are often growth stimulated by NDF, whereas SKBR3, and other ErbB2-overexpressing breast tumour cells are growth inhibited. We demonstrate here that in SKBR3 cells, NDF induces G1 progression but also causes a G2 delay from day 1 and apoptosis from days 2 – 3. G1 progression was associated with ErbB2 transactivation of ErbB3 and subsequent stimulation of the phosphatidylinositol 3-kinase (PI3K) pathway whereas apoptosis was dependent on p38 MAPK. Inhibition of ERK1/ERK2 had no effect on cell cycle progression or apoptosis. Activation of ErbB3 and PI3K was also seen with betacellulin (BTC) but not epidermal growth factor (EGF) and correlated with the growth effects of these ligands. All three ligands induced short-term activation of p38 MAPK in a c-Src-dependent manner. However, only NDF caused a second, c-Src-independent increase in p38 MAPK activity which was required for apoptosis.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

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
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Alessi DR, Cuenda A, Cohen P, Dudley DT and Saltiel AR. . 1995 J. Biol. Chem. 270: 27489–27494.

  • Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, DiFiore PP and Kraus MH. . 1995 Oncogene 10: 1813–1821.

  • Arteaga CL, Ramsey TT, Shawver LK and Guyer CA. . 1997 J. Biol. Chem. 272: 23247–23254.

  • Bacus SS, Huberman E, Chin D, Kiguchi K, Simpson S, Lippman M and Lupu R. . 1992 Cell Growth Differ. 3: 401–411.

  • Beerli RR and Hynes NE. . 1996 J. Biol. Chem. 271: 6071–6076.

  • Berger MS, Locher GW, Saurer S, Gullick WJ, Waterfield MD, Groner B and Hynes NE. . 1988 Cancer Res. 48: 1238–1243.

  • Bromberg JF, Brown C, Mendelsohn J and Darnell Jr JE. . 1998 Cell Growth Differ. 9: 505–512.

  • Burden S and Yarden Y. . 1997 Neuron 18: 847–855.

  • Coso OA, Chiariello M, Yu J-C, Teramoto H, Crespo P, Xu N, Miki T and Gutkind JS. . 1995 Cell 81: 1137–1146.

  • Daly JM, Jannot CB, Beerli RR, Graus-Porta D, Maurer FG and Hynes NE. . 1997 Cancer Res. 57: 3804–3811.

  • DiGiovanna MP and Stern DF. . 1995 Cancer Res. 55: 1946–1955.

  • Enslen H, Raingeaud J and Davis RJ. . 1998 J. Biol. Chem. 273: 1741–1748.

  • Fazioli F, Minichieollo L, Matoskova B, Wong WT and DiFiore PPD. . 1993 Mol. Cell. Biol. 13: 5814–5828.

  • Fedi P, Pierce JH, DiFiore PP and Kraus MH. . 1994 Mol. Cell Biol. 14: 492–500.

  • Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR and Tsichlis PN. . 1995 Cell 81: 727–736.

  • Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR, Connors RW and Bridges AJ. . 1995 Science 265: 1093–1095.

  • Gamett DC, Pearson G, Cerione RA and Friedberg I. . 1997 J. Biol. Chem. 272: 12052–12056.

  • Grasso AW, Wen D, Miller CM, Rhim JS, Pretlow TG and Kung H-J. . 1997 Oncogene 15: 2705–2716.

  • Graus-Porta D, Beerli RR and Hynes NE. . 1995 Mol. Cell. Biol. 15: 1182–1191.

  • Graus-Porta D, Beerli RR, Daly JM and Hynes NE. . 1997 EMBO J. 16: 1647–1655.

  • Hall A. . 1998 Science 279: 509–514.

  • Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, Pollok BA and Connelly PA. . 1996 J. Biol. Chem. 271: 695–701.

  • Hauck CR, Mayer TF, Lang F and Gulbins E. . 1998 EMBO J. 17: 443–454.

  • Hynes NE, Gerber HA, Saurer S and Groner B. . 1989 J. Cell. Biochem. 39: 167–173.

  • Hynes NE and Stern DF. . 1994 Biochim. Biophys. Acta. 1198: 165–184.

  • Jannot CB, Beerli RR, Mason S, Gullick WJ and Hynes NE. . 1996 Oncogene 13: 275–282.

  • Jones FE, Jerry JD, Guarino BC, Andrews GC and Stern D. . 1996 Cell Growth Differ. 7: 1031–1038.

  • Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Hynes NE and Yarden Y. . 1996 EMBO J. 15: 254–264.

  • Lane HA and Nigg EA. . 1996 J. Cell Biol. 135: 1701–1713.

  • Lax I, Mitra AK, Ravera C, Hurwitz DR, Rubinstein M, Ullrich A, Stroud RM and Schlessinger J. . 1991 J. Biol. Chem. 266: 13828–13833.

  • Levkowitz G, Klapper LN, Tzahar E, Freywald A, Sela M and Yarden Y. . 1996 Oncogene 12: 1117–1125.

  • Lewis GD, Lofgren JA, McMurtrey AE, Huijens A, Fendly BM, Bauer KD and Sliwkowsky MX. . 1996 Cancer Res. 56: 1457–1465.

  • Lisztwan J, Marti A, Sutterlüty H, Gstaiger M, Wirbelauer C and Krek W. . 1998 EMBO J. 17: 368–383.

  • Luttrell DK, Lee A, Lansing TJ, Crosby RM, Jung KD, Willard D, Luther M, Rodriguez M, Berman J and Gilmer TM. . 1994 Proc. Natl. Acad. Sci. USA 91: 83–87.

  • Marte BM, Jescke M, Graus-Porta D, Taverna D, Hofer P, Groner B, Yarden Y and Hynes NE. . 1995 Mol. Endocrinol. 9: 14–23.

  • Millar JBA, Blevitt J, Gerace L, Sadhu K, Featherstone C and Russell P. . 1991 Proc. Natl. Acad. Sci. USA 88: 10500–10504.

  • Minden A, Lin A, Claret F-X, Abo A and Karin M. . 1995 Cell 81: 1147–1157.

  • Missbach M, Jeschke M, Feyen J, Müller K, Green J and šuša M . 1999 Bone in press.

  • Murali R, Brennan PJ, Kieber-Emmons T and Greene MI. . 1996 Proc. Natl. Acad. Sci. USA 93: 6252–6257.

  • Muthuswamy SK, Siegel PM, Dankort DL, Webster MA and Muller WJ. . 1994 Mol. Cell. Biol. 14: 735–743.

  • Nurse P. . 1997 Cell 91: 865–867.

  • Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B and Hynes NE. . 1998 Mol. Cell. Biol. 18: 5042–5051.

  • Pages G, Lenormand P, L'Allemain G, Chambard JC, Meloche S and Pouyssegur J. . 1993 Proc. Natl. Acad. Sci. USA 90: 8319–8323.

  • Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Ben-Levy R and Yarden Y. . 1992 Cell 69: 205–216.

  • Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy L, Klapper S, Lavi S, Seger BJ, Ratzkin BJ, Sela M and Yarden Y. . 1996 EMBO J. 15: 2452–2467.

  • Prigent SA and Gullick WJ. . 1994 EMBO J. 13: 2831–2841.

  • Pullen N and Thomas G. . 1997 FEBS Lett. 410: 78–82.

  • Riese II DJ and Stern DF. . 1998 BioEssays 20: 41–48.

  • Salomon DD, Brandt R, Ciardiello F and Normanno N. . 1995 Crit. Rev. Oncol. Hematol. 19: 183–232.

  • Schwenger P, Bellosta P, Vietor I, Basilico C, Skolnik EY and Vilcek J. . 1997 Proc. Natl. Acad. Sci. USA 94: 2869–2873.

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keoth DE, Levin WJ, Stuart SG, Udove J and Press MF. . 1989 Science 244: 707–712.

  • Stover DR, Becker M, Liebetanz J and Lydon NB. . 1995 J. Biol Chem. 270: 15591–15597.

  • Takenaka K, Moriguchi T and Nishida E. . 1998 Science 280: 599–602.

  • Traxler PM, Furet P, Mett H, Buchdunger E, Meyer T and Lydon N. . 1996 J. Med. Chem. 39: 2285–2292.

  • Vanhaesebroeck B, Leevers SJ, Panayotou G and Waterfield MD. . 1997 TIBS 22: 267–272.

  • Vlahos CJ, Matter WF, Hui KY and Bronw RF. . 1994 J. Biol. Chem. 269: 5241–5248.

  • Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W and Ullrich A. . 1995 EMBO J. 14: 4267–4275.

  • Wang XS, Diener K, Manthey CL, Wang S, Rosenzweig JB, Delaney J, Cole CN, Chan-Hui P-Y, Mantlo N, Lichenstein HS, Zukowski M and Yao Z. . 1997 J. Biol. Chem. 272: 23668–23674.

  • Wang Y, Huang S, Sah VP, Ross J, Brown JH, Han J and Chien KR. . 1998 J. Biol. Chem. 273: 2161–2168.

  • Ward WHJ, Cook PN, Slater AM, Davies DH, Holdgate GA and Green LR. . 1994 Biochem. Pharmacol. 48: 659–666.

  • Whitmarsh AJ, Yang S-H, Su MS-S, Sharrocks AD and Davis RJ. . 1997 Mol. Cell. Biol. 17: 2360–2371.

  • Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME. . 1995 Science 270: 1326–1331.

  • Zechner D, Craig R, Hanford DS, McDonough PM, Sabbadini RA and Glembotski CC. . 1998 J. Biol. Chem. 273: 8232–8239.

  • Zrihan-Licht S, Lim J, Keydar I, Sliwkowski MX, Groopman JE and Avraham H. . 1997 J. Biol. Chem. 272: 1856–1863.

Download references

Acknowledgements

We thank Dr P Traxler and Dr J Green of Novartis for providing us with the ErbB and c-Src inhibitors, respectively. Thanks also to Dr W Krek and Dr P Dennis for their helpful suggestions on the manuscript. Dr John Daly and Dr Heidi Lane were partially supported by grants from the Swiss Cancer League.

Author information

Authors and Affiliations

  1. Friedrich Miescher Institute,, Basel, CH-4002, Switzerland

    John M Daly, Monilola A Olayioye, Agnes M-L Wong, Richard Neve, Heidi A Lane, Francisca G Maurer & Nancy E Hynes

Authors
  1. John M Daly
    View author publications

    Search author on:PubMed Google Scholar

  2. Monilola A Olayioye
    View author publications

    Search author on:PubMed Google Scholar

  3. Agnes M-L Wong
    View author publications

    Search author on:PubMed Google Scholar

  4. Richard Neve
    View author publications

    Search author on:PubMed Google Scholar

  5. Heidi A Lane
    View author publications

    Search author on:PubMed Google Scholar

  6. Francisca G Maurer
    View author publications

    Search author on:PubMed Google Scholar

  7. Nancy E Hynes
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Daly, J., Olayioye, M., Wong, AL. et al. NDF/heregulin-induced cell cycle changes and apoptosis in breast tumour cells: role of PI3 kinase and p38 MAP kinase pathways. Oncogene 18, 3440–3451 (1999). https://doi.org/10.1038/sj.onc.1202700

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.onc.1202700

Keywords

This article is cited by

Search

Advanced search

Quick links