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:

Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells

Abstract

The ErbB2 receptor tyrosine kinase is overexpressed in a variety of human tumours. In order to understand the mechanism by which ErbB2 mediates tumour proliferation we have functionally inactivated the receptor using an intracellularly expressed, ER-targeted single-chain antibody (scFV-5R). Inducible expression of scFv-5R in the ErbB2-overexpressing SKBr3 breast tumour cell line leads to loss of plasma membrane localized ErbB2. Simultaneously, the activity of ErbB3, MAP kinase and PKB/Akt decreased dramatically, suggesting that active ErbB2/ErbB3 dimers are necessary for sustained activity of these kinases. Loss of functional ErbB2 caused the SKBr3 tumour cells to accumulate in the G1 phase of the cell cycle. This was a result of reduction in CDK2 activity, which was mediated by a re-distribution of p27Kip1 from sequestering complexes to cyclin E/CDK2 complexes. The level of c-Myc and D-cyclins, proteins involved in p27Kip1 sequestration, decreased in the absence of functional ErbB2. Ectopic expression of c-Myc led to an increase in D cyclin levels, CDK2 activity and resulted in a partial G1 rescue. We propose that c-Myc is a primary effector of ErbB2-mediated oncogenicity and functions to prevent normal p27Kip1 control of cyclinE/CDK2.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

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

Similar content being viewed by others

References

  • Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronsen SA, Di Fiore 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

  • Beerli RR, Wels W and Hynes NE . 1994 J Biol Chem 269: 23931–23936

  • Beerli RR, Graus-Porta D, Woods-Cook K, Chen X, Yarden Y and Hynes NE . 1995 Mol Cell Biol 15: 6496–6505

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

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

  • Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, Reed S, Sicinski P, Bartek J and Eilers M . 1999 EMBO J 19: 5321–5333

  • Burgering BM and Coffer PJ . 1995 Nature 376: 599–602

  • Carraway III KL and Cantley LC . 1994 Cell 78: 5–8

  • 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 Nature Med 3: 227–230

  • Cheathem B, Vlahos CJ, Cheathem L, Wang L, Blenis J and Khan CR . 1994 Mol Cell Biol 14: 4902–4911

  • Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM and Sherr CJ . 1999 EMBO J 18: 1571–1583

  • Chung J, Grammar TC, Lemon KP, Kazlauskas A and Blenis J . 1994 Nature 370: 71–75

  • Czubayko F, Downing SG, Hsieh SS, Goldstein DJ, Lu PY, Trapnell BC and Wellstein A . 1997 Gene Ther 4: 943–949

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

  • Daly JM, Olayioye MA, Wong AM-L, Neve R, Lane HA, Maurer FG and Hynes NE . 1999 Oncogene 18: 3440–3451

  • Diehl JA, Cheng M, Roussel MF and Sherr CJ . 1998 Genes Dev 12: 3499–3511

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

  • Ebbinghaus SW, Gee JE, Rodu B, Mayfield CA, Sanders G and Miller DM . 1993 J Clin Invest 92: 2433–2439

  • Escot C, Theillet C, Lidereau R, Spyratos F, Champene MH, Gest J and Callahan R . 1986 Proc Natl Acad Sci USA 83: 4834–4838

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

  • Fiddes RJ, Janes PW, Sivertsen SP, Sutherland RL, Musgrove EA and Daly RJ . 1998 Oncogene 16: 2803–2813

  • Grana X, Garriga J and Mayol X . 1998 Oncogene 17: 3365–3383

  • 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

  • Hardy S, Kitamura M, Harris-Stansil T, Dai Y and Phipps ML . 1997 J Virol 71: 1842–1849

  • Harwerth IM, Wels W, Marte BM and Hynes NE . 1992 J Biol Chem 267: 15160–15167

  • 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: 275–283

  • Juhl H, Downing SG, Wellstein A and Czubayko F . 1997 J Biol Chem 272: 29482–29486

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

  • Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J and Evan G . 1997 Nature 385: 544–548

  • Keyomarsi K and Pardee AB . 1993 Proc Natl Acad Sci USA 90: 1112–1116

  • Leone G, DeGregori J, Sears R, Jakoi L and Nevins JR . 1997 Nature 387: 422–426

  • Marcu KB, Bossone SA and Patel AJ . 1992 Annu Rev Biochem 61: 809–860

  • Meyerson M and Harlow E . 1994 Mol Cell Biol 14: 2077–2086

  • Nigg EA . 1995 BioEssays 17: 471–480

  • Paulus W, Baur I, Boyce FM, Breakfield XO and Reeves SA . 1996 J Virol 70: 62–67

  • Pawson T and Scott JD . 1997 Science 278: 2075–2080

  • Perez-Roger I, Kim S-H, Griffiths B, Sewing A and Land H . 1999 EMBO J 18: 5310–5320

  • 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

  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM and Koff A . 1994 Genes Dev 8: 9–22

  • Poon RY, Toyoshima H and Hunter T . 1995 Mol Biol Cell 6: 1197–1213

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

  • Schuuring E, Verhoeven E, Mooi WJ and Michalides RJAM . 1992 Oncogene 7: 355–361

  • Sears R, Lone G, DeGregori J and Nevins JR . 1999 Mol Cell 3: 169–179

  • Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB and Gray JW . 1999 Nat Genet 21: 99–102

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

  • Sherr CJ and Roberts JM . 1999 Genes Dev 13: 1501–1512

  • Siegel M, Ryan ED, Cardiff RD and Muller WJ . 1999 EMBO J 18: 2149–2164

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A and McGuire WL . 1987 Science 235: 177–182

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

  • Spencer CA and Groudine M . 1991 Adv Cancer Res 56: 1–48

  • Stern DF, Kamps MP and Cao H . 1988 Mol Cell Biol 8: 3969–3973

  • Ullrich A and Schlessinger J . 1990 Cell 61: 203–212

  • Vlach J, Hennecke S, Alevizopoulos K, Conti D and Amati B . 1996 EMBO J 15: 6595–6604

  • Waterman H, Alroy I, Strano S, Seger R and Yarden Y . 1999 EMBO J 18: 3348–3358

  • Wels W, Harwerth I-M, Zwickl M, Hardman N, Groner B and Hynes NE . 1992 Bio/Technology 10: 1128–1132

  • Yancopoulos GD, Nisen PD, Tesfaye A, Kohl NE, Goldfarb MP and Alt FW . 1985 Proc Natl Acad Sci USA 82: 5455–5459

  • Zhang K, Sun J, Liu N, Wen D, Chang A, Thomason A and Yoshinage SK . 1996 J Biol Chem 271: 3884–3890

Download references

Acknowledgements

Richard Neve was partially supported by a grant from the Basel Cancer League. Heidi Lane and John Daly were partially supported by grants from the Swiss Cancer League. We thank Thomas Holbro, Ulrich Müller, Chris Benz, Bruno Amati, Trevor Littlewood, Peter Traxler, Alain Marti, and Matthias Senften for helpful discussions and reagents and Sinisa Volarevic for invaluable input.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neve, R., Sutterlüty, H., Pullen, N. et al. Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells. Oncogene 19, 1647–1656 (2000). https://doi.org/10.1038/sj.onc.1203470

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203470

Keywords

This article is cited by

Search

Quick links