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Tumor-specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal transduction pathways

Cancer Gene Therapy volume 11, pages 28–40 (2004)Cite this article

Abstract

Adenoviral gene expression that is repressed by p53 in nontransformed cells could provide a tumor-specific gene therapy approach for a large subset of tumors. Adenoviral infection in vivo induces stabilization of p53, which can be utilized for a strategy that includes p53-dependent expression of a transcriptional repressor and a target promoter, which is highly susceptible for transcriptional repression. Therefore, we constructed different versions of CMV-promoters (CMVgal) with binding sites for GAL4-DBD and investigated 11 GAL4-DBD fusion proteins to elucidate the most effective repressor domain to silence CMVgal activity.The transcriptional repressor GAL4-KRAB-A under control of a p53-dependent promoter facilitates strong CMVgal-mediated gene expression specifically in p53 mutant cells by a double-recombinant adenoviral vector (Ad-RGCdR). GAL4-KRAB-A mediates strong transcriptional repression of Ad-RGCdR in p53 wild-type cells, which could be further enhanced by preactivation of p53-signalling following low-dose chemotherapy prior to adenoviral infection. By utilizing p53 signalling involved in chemotherapy and adenoviral infection, more than 99% of Ad-RGCdR gene expression could be repressed in p53 wild-type cells. Controlled gene expression from CMVgal promoters by transcriptional repression utilizing functional p53 signalling thus provides a very effective tool for tumor-specific adenoviral gene therapy.

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Abbreviations

DBD:

DNA-binding domain

RGC:

ribosomal gene cluster

MOI:

multiplicity of infection

mt:

mutant

wt:

wild type

X-gal:

5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside

dep.:

dependent

therap.:

therapeutic

Cons.:

consensus

Seq.:

sequence

Luc.:

luciferase

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Acknowledgements

This research was supported by a grant of the Wilhelm Sander Stiftung (98.046.2).

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Authors and Affiliations

  1. Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl Neuberg Str. 1, Hannover, 30625, Germany

    Florian Kühnel, Lars Zender, Thomas Wirth, Bernd Schulte, Christian Trautwein, Michael Manns & Stefan Kubicka

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  1. Florian Kühnel
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Correspondence to Stefan Kubicka.

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Kühnel, F., Zender, L., Wirth, T. et al. Tumor-specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal transduction pathways. Cancer Gene Ther 11, 28–40 (2004). https://doi.org/10.1038/sj.cgt.7700632

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