Selective killing of cancer cells based on translational control of a suicide gene

DeFatta, Robert J.; Li, Yuan; Benedetti, Arrigo De

doi:10.1038/sj.cgt.7700468

Cited by 34 publications

(44 citation statements)

References 27 publications

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“…Systemic administration of the prodrug gancyclovir would then be expected to be benign in normal tissues, but converted into its toxic phosphorylated product only in tumor cells. This concept was demonstrated using the 5 0 UTR of rat FGF2 (619 bases, stability of À55 kcal/mol) upstream of the gancyclovir open reading frame (DeFatta et al, 2002). These experiments demonstrated that tumor cells expressing the chimeric HSV-TK RNA could be killed at up to 500-fold lower concentrations of gancyclovir than normal cells, in a manner that was dependent on eIF4E expression (DeFatta et al, 2002).…”

Section: Selective Translational Expression Of Killer Genes In Tumor mentioning

confidence: 89%

“…This concept was demonstrated using the 5 0 UTR of rat FGF2 (619 bases, stability of À55 kcal/mol) upstream of the gancyclovir open reading frame (DeFatta et al, 2002). These experiments demonstrated that tumor cells expressing the chimeric HSV-TK RNA could be killed at up to 500-fold lower concentrations of gancyclovir than normal cells, in a manner that was dependent on eIF4E expression (DeFatta et al, 2002). This concept was extended by using either a lentivirus or adenovirus (Mathis et al, 2006) to deliver such constructs, as well as adding a prostate specific promoter to drive expression specifically in prostate epithelial cells .…”

Section: Selective Translational Expression Of Killer Genes In Tumor mentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies

Bilanges

Stokoe

2007

Oncogene

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Section: Selective Translational Expression Of Killer Genes In Tumor mentioning

confidence: 89%

Section: Selective Translational Expression Of Killer Genes In Tumor mentioning

confidence: 99%

Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies

Bilanges

Stokoe

2007

Oncogene

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“…eIF4E should also prove to be central to our understanding of P-bodies and mRNA degradation because P-bodies lack ribosomes and all translation initiation factors except eIF4E (37). The involvement of eIF4E in malignant transformation and metastasis is the subject of intense research (38), including its utility as a marker for cancer stage and potential to serve as a target for novel anticancer therapies (39,40). Further knowledge of the factors that influence eIF4E function should aid in our understanding of malignant transformation and in the development of therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

eIF4E: New Family Members, New Binding Partners, New Roles

Rhoads

2009

Journal of Biological Chemistry

146

169

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Eukaryotic initiation factor 4E (eIF4E) has long been known as the cap-binding protein that participates in recruitment of mRNA to the ribosome. A number of recent advances have not only increased our understanding of how eIF4E acts in translation but also uncovered non-translational roles. New structures have been determined for eIF4E in complex with various ligands and for other cap-binding proteins. We have also learned that most eukaryotic organisms express multiple eIF4E family members, some involved in general translation but others having specialized functions, including repression of translation. A number of new eIF4E-binding proteins have been reported, some of which tether it to specific mRNAs.The 7-methylguanosine-containing "cap" plays an essential role at each stage of the mRNA "life cycle": transcription, splicing, nuclear export, translation, translational repression, and degradation. This is mediated by specific cap-binding proteins, of which at least 10 have been discovered so far (supplemental Table S1). The most widely studied and best understood of these cap-binding proteins is eIF4E.2 eIF4E was discovered as a protein that promotes translation initiation, and most of the work on its structure, function, and regulation has been performed with this role in mind. As a canonical initiation factor involved in recruitment of mRNA to the ribosome, eIF4E has the potential to influence expression of virtually every protein in the cell. It is against this backdrop of eIF4E serving as a translational enhancer that discoveries over the past decade have been so surprising, that eIF4E can also function as a translational repressor. Another unexpected result of recent research is that nearly all eukaryotes express multiple eIF4E family members and that they can have different functions in the cell. A third research trend has been the discovery of new eIF4E-binding partners, some of which tether eIF4E to specific mRNAs. This minireview touches on all of these new directions in eIF4E research. Role of eIF4E in TranslationRecruitment of mRNA to the 43 S initiation complex to form the 48 S initiation complex requires eIF3, the poly(A)-binding protein, and the eIF4 proteins (Fig. 1B) (1). The eIF4 factors consist of eIF4A, a 46-kDa RNA helicase; eIF4B, a 70-kDa RNA-binding and RNA-annealing protein; eIF4E, a 25-kDa cap-binding protein; eIF4H, a 25-kDa protein that acts with eIF4B to stimulate eIF4A helicase activity; and eIF4G, a 185-kDa protein that co-localizes all of the other proteins involved in mRNA recruitment on the 40 S subunit.3 At least four cis-acting elements affect the efficiency of mRNA translation: the cap, the poly(A) tail, sequence elements in the 5Ј-UTR, and sequence elements in the 3Ј-UTR. It is well established that eIF4E stimulates translation of capped mRNAs, but mRNAs differ in their dependence on eIF4E. For instance, mRNAs with extensive 5Ј-UTR secondary structure have a greater requirement for the eIF4A-based unwinding machinery recruited by eIF4E (Fig. 1B) (2).The tertiary structures ...

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“…4,10 Previous studies have illustrated an increase of the intrinsic levels eIF4E in a variety of malignancies, including prostate cancer. 4 Elevations in eIF4E lead to increases in cell proliferation, suppression of apoptosis and other characteristics associated with neoplastic transformation.…”

Section: Introductionmentioning

confidence: 99%

“…13 The 5 0 UTRs from FGF-2 and ODC have previously been shown to contain extensive, stable secondary structures, and it has previously been reported that their translation is tightly controlled. 10,13,14 We found that two out of the three 5 0 UTR tested in vitro showed excellent potential for tumor-specific targeting based on eIF4E levels and the extent of enhanced green fluorescent protein (GFP) expression. Infection of prostate tumors in the PTEN À/À transgenic mouse model confirmed this impression.…”

Section: Introductionmentioning

confidence: 99%

Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice

et al. 2011

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In this study, we have taken advantage of over-expression of eukaryotic translation initiation factor 4E (eIF4E) in prostate cancer cells to design a viral-based targeting system of prostate cancer. Three different lengths of 5 0 -untranslated regions (5 0 UTRs) derived from either fibroblast growth factor-2 (FU-FGF2-GW) or ornithine decarboxylase (FU-ODC 149 -GW and FU-ODC 274 -GW) were inserted upstream of enhanced green fluorescent protein (GFP) gene in a lentiviral backbone. Both nonmalignant control (PNT1B and BPH-1) and neoplastic (LNCaP, C4-2, DU145 and PC-3) prostate cell lines were transfected with each plasmid or virus alone, or in the presence of siRNA against eIF4E, and their expression was monitored via GFP protein levels. Two 5 0 UTRs (FU-FGF2-GW and FU-ODC-GW) were selected as being most sensitive to eIF4E status. Lentiviruses containing these sequences were injected directly into the prostates of PTEN À/À (tumor-bearing) and control mice. Immunofluorescence data and western blot analyses determined that a lentivirus containing a 5 0 UTR derived from FGF-2 is the best candidate for directing selective gene expression in the prostate tumors of PTEN À/À mice in vivo. This study demonstrates that judicious selection of a complex 5 0 UTR can enhance selective targeting of viral-based gene therapies for prostate cancer.

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Selective killing of cancer cells based on translational control of a suicide gene

Cited by 34 publications

References 27 publications

Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies

Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies

eIF4E: New Family Members, New Binding Partners, New Roles

Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice

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