title: Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma.
abstract: We previously demonstrated that restoration of TP53 activity in anaplastic thyroid carcinoma inhibits cell growth and induces expression of thyroid differentiation markers. Here, we investigated whether TP53 status may condition the expression of therapeutic genes driven by retroviral LTR or tissue-specific enhancer elements. The TP53-defective ARO anaplastic thyroid carcinoma cells were transfected with TP53(Val135), which exhibits wild-type activity at 32 degrees C, and transduced with retroviral vectors, in which therapeutic genes were driven either by wild-type LTR or by a reshuffled LTR containing thyroglobulin (TG) enhancer. Both at 37 and 32 degrees C, expression of transgenes driven by TG enhancer was 10-fold lower than that obtained with wild-type LTR retroviral vector. TP53(Val135) transfer into ARO cells repressed transcription from wild-type LTR but increased expression of TG-driven therapeutic genes. This effect was markedly enhanced by cell culture at 32 degrees C and by TSH treatment. Cytotoxic effects shown after ganciclovir treatment paralleled therapeutic gene expression levels. In conclusion, TP53 status in the tumor cell can influence expression of therapeutic genes. When using retroviral-vector-based gene therapy, wild-type LTR vectors should be employed to target TP53-defective tumors, whereas thyroid-specific promoters should be used for transcriptional targeting of thyroid carcinomas carrying wild-type TP53.
authors.affiliation: Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, I-35121 Padova, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Barzon
authors.forename: Elisa
authors.initials: E
authors.lastname: Gnatta
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
authors.forename: Marta
authors.initials: M
authors.lastname: Trevisan
authors.forename: Fabiola
authors.initials: F
authors.lastname: Moretti
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pontecorvi
authors.forename: Marco
authors.initials: M
authors.lastname: Boscaro
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000628:therapy*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D015774:Ganciclovir / Q000494:pharmacology; D016158:Genes, p53 / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D013954:Thyroglobulin / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000628:therapy*; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D012313:RNA; D013954:Thyroglobulin; D015774:Ganciclovir