Regulation of cellular response to cisplatin-induced DNA damage and DNA repair in cells overexpressing p185erbB-2 is dependent on the ras signaling pathway (original) (raw)

Oncogene volume 14, pages 1827–1835 (1997)Cite this article

Abstract

We have examined the role of erbB-2 expression in the modulation of cellular toxicity to cisplatin. We have demonstrated that treatment of NIH3T3-erbB-2 cells, which overexpress the p185erbB-2 product of the human erbB-2 gene, with a monoclonal antibody directed against the extracellular domain (TAb-250), results in enhanced cisplatin cytotoxicity. A similar enhancement was obtained when cells were exposed to herbimycin A and its analogue CP127 374, both of which inhibit tyrosine kinase activity. Using the host cell reactivation (HCR) of reporter gene expression from cisplatin-damaged plasmid and unscheduled DNA synthesis (UDS) following cisplatin treatment of cells, we have found that modulation of erbB-2 by TAb-250 was associated with inhibition of DNA repair. TAb-250 alone, under conditions which modulate DNA repair, slightly reduces the S-phase of the cell cycle, while cisplatin induced arrest at S and G2 phases. Combination of TAb-250 and cisplatin only slightly prevented cisplatin-induced S and G2 blocks. Since the ras pathway is one of the major signaling components coupled to erbB-2, we have examined the role of ras in DNA repair regulation. Transient expression of a ras dominant negative mutant, Asn-17-rasH, prevents DNA repair modulation by TAb-250, suggesting that the erbB-2 receptor regulates DNA repair mechanism(s), at least in part, through ras-coupled pathway(s).

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

Access options

Subscribe to this journal

Receive 50 print issues and online access

$259.00 per year

only $5.18 per issue

Buy this article

USD 39.95

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

Additional access options:

Similar content being viewed by others

Author information

Authors and Affiliations

  1. Departments of Medicine, Lady Davis Institute of the Sir Mortimer B Davis Jewish General Hospital, Oncology and McGill Translational Center for Cancer, McGill University, 3755, Côte Ste-Catherine Road, Montreal, H3T 1E2, Canada, USA
    Lily Yen, Nie Zeng-Rong, Xiao-Li You, Stéphane Richard & Moulay A Alaoui-Jamali
  2. Department of Oncology Research, Strategic Research Unit I, Berlex Bio-Sciences, Inc., Richmond, 94804-0099, CA, USA
    Beatrice C Langton-Webster

Authors

  1. Lily Yen
  2. Nie Zeng-Rong
  3. Xiao-Li You
  4. Stéphane Richard
  5. Beatrice C Langton-Webster
  6. Moulay A Alaoui-Jamali

Rights and permissions

About this article

Cite this article

Yen, L., Zeng-Rong, N., You, XL. et al. Regulation of cellular response to cisplatin-induced DNA damage and DNA repair in cells overexpressing p185erbB-2 is dependent on the ras signaling pathway.Oncogene 14, 1827–1835 (1997). https://doi.org/10.1038/sj.onc.1201019

Download citation

Keywords

This article is cited by