title: Testis-specific HMG-domain protein alters the responses of cells to cisplatin.
abstract: Cisplatin is an effective agent for the treatment of testicular cancer. In the present study with mouse testicular teratocarcinoma cell extracts, we observed a deficiency in nucleotide excision repair (NER) of a DNA probe bearing a cisplatin 1,2-d(GpG) intrastrand cross-link. In contrast, repair of the cisplatin 1,3-d(GpTpG) intrastrand cross-link was still active in these cell extracts. A current working hypothesis is that complexes of HMG-domain proteins with the major cisplatin 1,2-intrastrand cross-links could enhance cisplatin cytotoxicity by blocking repair of these lesions on the genome. The family of HMG-domain proteins include a testis-specific protein, tsHMG, which might account for the altered NER in testicular cells. To test this possibility, a human cervical carcinoma cell line (HeLa) was constructed which ectopically expressed tsHMG under the control of an inducible promoter. Microscopic examination of tsHMG expression and cisplatin-induced apoptosis on a cellular level revealed that the nuclear protein did indeed modulate the cytotoxic consequences of cisplatin treatment. Also, tsHMG enhanced transcription inhibition by cisplatin. These results reveal that an HMG-domain protein can affect cellular responses to cisplatin and may be relevant to the clinical observation that cancer cells in specific tissues are particularly sensitive to cisplatin.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA.
authors.forename: Deborah B
authors.initials: DB
authors.lastname: Zamble
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mikata
authors.forename: Christina H
authors.initials: CH
authors.lastname: Eng
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sandman
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D018736:DNA Adducts; D049452:Green Fluorescent Proteins; D024002:HMGB Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000187:drug effects; D018243:Teratocarcinoma / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics; D013737:Testis / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D018736:DNA Adducts; D024002:HMGB Proteins; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D002945:Cisplatin