title: Accumulation of mutant p53(V143A) modulates the growth, clonogenicity, and radiochemosensitivity of malignant glioma cells independent of endogenous p53 status.
abstract: Alterations of the p53 gene have been attributed a major role in the development and resistance to therapy of several human cancers. Accumulation of p53 in tumor cells may result from mutations associated with prolonged half-life or from stabilization of wild-type p53 by different mechanisms. To address the role of p53 accumulation in the response of malignant glioma cells to radiochemotherapy, we expressed the p53 mutant p53(V143A) in five human malignant glioma cell lines with different genetic and functional p53 status. Accumulation of p53(V143A) modulated proliferation in three and clonogenicity in four of five cell lines without a clear pattern with regard to their endogenous p53 status. p53(V143A) inhibited the camptothecin-induced accumulation of p21(WAF1/CIP1) in cell lines with p53 functional wild-type activity, but not in cell lines lacking p53 activity, consistent with a transdominant-negative effect of p53(V143A). Irradiation induced a moderate G2/M arrest in all cell lines, irrespective of the p53 status, that was unaffected by p53(V143A). Radiosensitivity as well as sensitivity to BCNU, teniposide (VM26), topotecan, vincristine, Taxol, and cisplatin both in cytotoxic cell death and in clonogenic cell death was unchanged in p53(V143A)-transfected cells with few exceptions. These data do not support the hypothesis that accumulation of mutant p53 is a major determinant of the response to adjuvant radiochemotherapy in human malignant glioma cells.
authors.affiliation: Department of Neurology, University of Tübingen, Tübingen, 72076, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bartussek
authors.forename: U
authors.initials: U
authors.lastname: Naumann
authors.forename: M
authors.initials: M
authors.lastname: Weller
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001932:Brain Neoplasms; D002166:Camptothecin / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D002999:Clone Cells / Q000502:physiology; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005799:Genes, Dominant; D005910:Glioma; D006801:Humans; D066298:In Vitro Techniques; D017239:Paclitaxel / Q000494:pharmacology; D017354:Point Mutation; D011878:Radiotherapy; D013713:Teniposide / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; D019772:Topotecan; D013713:Teniposide; D017239:Paclitaxel; D002945:Cisplatin; D002330:Carmustine; D002166:Camptothecin