title: Composing a Tumor Specific Bacterial Promoter.
abstract: Systemically applied Salmonella enterica spp. have been shown to invade and colonize neoplastic tissues where it retards the growth of many tumors. This offers the possibility to use the bacteria as a vehicle for the tumor specific delivery of therapeutic molecules. Specificity of such delivery is solely depending on promoter sequences that control the production of a target molecule. We have established the functional structure of bacterial promoters that are transcriptionally active exclusively in tumor tissues after systemic application. We observed that the specific transcriptional activation is accomplished by a combination of a weak basal promoter and a strong FNR binding site. This represents a minimal set of control elements required for such activation. In natural promoters, additional DNA remodeling elements are found that alter the level of transcription quantitatively. Inefficiency of the basal promoter ensures the absence of transcription outside tumors. As a proof of concept, we compiled an artificial promoter sequence from individual motifs representing FNR and basal promoter and showed specific activation in a tumor microenvironment. Our results open possibilities for the generation of promoters with an adjusted level of expression of target proteins in particular for applications in bacterial tumor therapy.
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Deyneko
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kasnitz
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Leschner
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.|Institute of Immunology, Medical School Hannover, Hannover, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001483:Base Sequence; D005260:Female; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000235:genetics*; D059372:Nucleotide Motifs / Q000235:genetics; D011401:Promoter Regions, Genetic; D019779:Salmonella enterica / Q000235:genetics*; D013154:Spleen / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D049452:Green Fluorescent Proteins