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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.

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  • Authors+Show Affiliations

    ,

    Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, I-35121 Padova, Italy.

    , , , , , ,

    Source

    Cancer gene therapy 12:4 2005 Apr pg 381-8

    MeSH

    Animals
    Carcinoma
    Cell Differentiation
    Cell Line, Tumor
    Dose-Response Relationship, Drug
    Enhancer Elements, Genetic
    Enzyme-Linked Immunosorbent Assay
    Ganciclovir
    Genes, p53
    Genetic Vectors
    Humans
    Inhibitory Concentration 50
    Mice
    Microscopy, Fluorescence
    Promoter Regions, Genetic
    RNA
    Retroviridae
    Reverse Transcriptase Polymerase Chain Reaction
    Temperature
    Thyroglobulin
    Thyroid Neoplasms
    Time Factors
    Transcription, Genetic
    Tumor Suppressor Protein p53

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    15650765

    Citation

    Barzon, Luisa, et al. "Modulation of Retrovirally Driven Therapeutic Genes By Mutant TP53 in Anaplastic Thyroid Carcinoma." Cancer Gene Therapy, vol. 12, no. 4, 2005, pp. 381-8.
    Barzon L, Gnatta E, Castagliuolo I, et al. Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma. Cancer Gene Ther. 2005;12(4):381-8.
    Barzon, L., Gnatta, E., Castagliuolo, I., Trevisan, M., Moretti, F., Pontecorvi, A., ... Palù, G. (2005). Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma. Cancer Gene Therapy, 12(4), pp. 381-8.
    Barzon L, et al. Modulation of Retrovirally Driven Therapeutic Genes By Mutant TP53 in Anaplastic Thyroid Carcinoma. Cancer Gene Ther. 2005;12(4):381-8. PubMed PMID: 15650765.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma. AU - Barzon,Luisa, AU - Gnatta,Elisa, AU - Castagliuolo,Ignazio, AU - Trevisan,Marta, AU - Moretti,Fabiola, AU - Pontecorvi,Alfredo, AU - Boscaro,Marco, AU - Palù,Giorgio, PY - 2005/1/15/pubmed PY - 2005/6/29/medline PY - 2005/1/15/entrez SP - 381 EP - 8 JF - Cancer gene therapy JO - Cancer Gene Ther. VL - 12 IS - 4 N2 - 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. SN - 0929-1903 UR - https://www.unboundmedicine.com/medline/citation/15650765/Modulation_of_retrovirally_driven_therapeutic_genes_by_mutant_TP53_in_anaplastic_thyroid_carcinoma_ L2 - http://dx.doi.org/10.1038/sj.cgt.7700789 DB - PRIME DP - Unbound Medicine ER -