title: Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms.
abstract: Mutant p53 frequently accumulates in cancer cells and promotes tumor cell invasion, as part of its gain of function. Its accumulation is partially due to enhanced stability, but little is known about how the mRNA levels of mutant p53 can be regulated. Likewise, the impact of cancer therapy on the levels of mutant p53 is poorly understood. We show here that the anthracyclines doxorubicin, daunorubicin and epirubicin further increase the amounts of mutant p53 mRNA and protein in cancer cells. Moreover, we show for the first time that the transcription factor E2F1 associates with the promoter DNA of TP53. Upon genotoxic treatment, E2F1 contributed to the expression of mutant p53, both directly and through induction of TAp73. In contrast, the anthracycline idarubicin and also another topoisomerase inhibitor, etoposide, failed to increase the levels of p53 mRNA, despite their ability to induce the synthesis of TAp73 mRNA. Instead, a natural antisense transcript of TP53, WRAP53, was strongly augmented by idarubicin and etoposide, but only less so by the other anthracyclines under study. RNA corresponding to the first exon of WRAP53 was mainly found in cell nuclei and it reduced the levels of mutant p53. Taken together, this suggests a reciprocal activation pattern of TP53 and WRAP53 by different chemotherapeutics. Reducing the levels of mutant p53 by small-interfering RNA increased chemosensitivity, and idarubicin prevented cell survival more efficiently than the mutant p53-inducing doxorubicin. We conclude that even closely related anthracyclines induce the synthesis of different, opposing transcripts from the TP53 locus. When using these drugs for cancer therapy, the increased levels of mutant p53 may augment its gain of function and thus favor unwanted chemoresistance and tumor progression.
authors: Department of Molecular Oncology, Göttingen Center of Molecular Biosciences-GZMB, Ernst Caspari Haus, University of Göttingen, Göttingen, Germany.
authors: M
authors: M
authors: Bug
authors: M
authors: M
authors: Dobbelstein
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology*; D002478:Cells, Cultured; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000502:physiology*; D016158:Genes, p53; D006801:Humans; D018832:Molecular Chaperones; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000096:biosynthesis; D059003:Topoisomerase Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018943:Anthracyclines; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D018832:Molecular Chaperones; D059003:Topoisomerase Inhibitors; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D019098:Telomerase; C535133:WRAP53 protein, human