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  • Title: Regulation of cellular response to cisplatin-induced DNA damage and DNA repair in cells overexpressing p185(erbB-2) is dependent on the ras signaling pathway.
    Author: Yen L, Nie ZR, You XL, Richard S, Langton-Webster BC, Alaoui-Jamali MA.
    Journal: Oncogene; 1997 Apr 17; 14(15):1827-35. PubMed ID: 9150389.
    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 p185(erbB-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-ras(H), 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).
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