Poor intercellular transport and absence of enhanced antiproliferative activity after non‐viral gene transfer of VP22‐P53 or P53‐VP22 fusions into p53 null cell lines <i>in vitro</i> or <i>in vivo</i>

Zavaglia, David; Lin, Erh-Hsuan; Josserand, Véronique; Pluquet, Olivier; Hainaut, Pierre; Favrot, Marie‐Christine; Coll, Jean‐Luc

doi:10.1002/jgm.741

Cited by 8 publications

(10 citation statements)

References 38 publications

(63 reference statements)

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“…However, the transfection efficiency is still low (o1% of the tumor cells), but we previously demonstrated that it is sufficient to successfully deliver p53-, bax-or p27-encoding plasmids. [26][27][28] In this study, we show that despite this very low transfection efficiency, a significant reduction of tumor growth can be observed after direct intratumoral injection of HERV-W-or GALV-, but not RD-FMG-encoding plasmids. This strong antitumor response suggests that FMG genes and especially HERV-W and GALV are very potent and promising tools for the treatment of human lung tumors, especially in immunecompetent animals where we know that this direct cell-killing activity of FMG will also be supported by release of highly immunogenic exosome-like vesicles.…”

Section: Fmg-mediated Tumor Therapy E-h Lin Et Almentioning

confidence: 63%

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Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer

et al. 2009

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Fusogenic membrane glycoproteins (FMGs) are viral envelope proteins, which bind surface receptors and induce fusion of the cell membrane. An FMG-transfected cell will fuse with neighbor cells, thus forming syncytia that die within 5 days. In this report, plasmids encoding for FMGs from Human Endogenous Retrovirus-W (HERV-W) was compared with Gibbon Ape Leukemia Virus (GALV) and feline endogenous virus RD-114 (RD). These plasmids were transfected in human non-small-cell lung cancer (NSCLC) cells in vitro or directly injected into tumors in mice. All FMGs induced the formation of syncytia containing around 50 cells. HERV-W or GALV FMGs decreased up to 80% of cell viability in vitro and inhibited tumor growth in vivo (60-70% reduction). In contrast, RD FMG was not efficient. Apoptosis played a role in the death of the syncytia, but addition of the caspase inhibitor Z-VAD-fmk had no effect, suggesting that apoptosis is not the only mechanism responsible for FMG-induced cell death. Altogether, our results demonstrate that even at very low transfection efficiency, the antitumor activity of HERV-W FMG is as effective as that of GALV in vitro and in vivo for the treatment of human lung tumors.

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Section: Fmg-mediated Tumor Therapy E-h Lin Et Almentioning

confidence: 63%

“…29 Fusion proteins between VP22 and a therapeutic polypeptide were thus successfully used for in vivo tumor therapy although conflicting results have also been reported. 27,28,[30][31][32][33][34][35] Positive gene therapy results using suicide genes like the herpes simplex type-1 thymidine …”

Section: Discussionmentioning

confidence: 99%

Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer

et al. 2009

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“…The transport of chimeric proteins consisting of VP22 covalently bound to green fluorescent protein (GFP) or other proteins from cell to cell has been disputed (1,2,4,10,17,20,22,28,33,38,55,58,59). The conflicting reports remain to be resolved, but it should be pointed out that some proteins are readily extracted during methanol fixation of cells and that covalently bound polypeptides of a size nearly equivalent to or larger than VP22 could be expected to change the properties of the protein.…”

mentioning

confidence: 99%

Replication-Competent Herpes Simplex Virus 1 Isolates Selected from Cells Transfected with a Bacterial Artificial Chromosome DNA Lacking Only the U _L 49 Gene Vary with Respect to the Defect in the U _L 41 Gene Encoding Host Shutoff RNase

Sciortino

Taddeo

Giuffrè-Cuculletto

et al. 2007

J Virol

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To generate a null U L 49 gene mutant of herpes simplex virus 1 (HSV-1), we deleted from the viral DNA, encoded as a bacterial artificial chromosome (BAC), the U L 49 open reading frame and, in a second step, restored it. Upon transfection into Vero cells, the BAC-⌬U L 49 DNA yielded foci of degenerated cells that could not be expanded and a few replication-competent clones. The replication-competent viral clones derived from independent transfections yielded viruses that expressed genes with some delay, produced smaller plaques, and gave lower yields than wild-type virus. A key finding is that the independently derived replication-competent viruses lacked the virion host shutoff (vhs) activity expressed by the RNase encoded by the U L 41 gene. One mutant virus expressed no vhs protein, whereas two others, derived from independent transfections, produced truncated vhs proteins consistent with the spontaneous in-frame deletion. In contrast, cells infected with the virus recovered upon transfection of the BAC-U L 49R DNA (R-U L 49) accumulated a full-length vhs protein, indicating that in the parental BAC-⌬U L 49 DNA, the U L 41 gene was intact. We conclude that expression of the vhs protein in the absence of U L 49 protein is lethal, a conclusion bolstered by the evidence reported elsewhere that in transfected cells vhs requires both VP16 and VP22, the product of U L 49, to be neutralized.Of the 84 different known proteins encoded by herpes simplex virus 1 (HSV-1), at least 4 proteins, all located in the tegument of the virion, interact with mRNAs. Of these, the proteins encoded by the U S 11, U L 47, and U L 49 open reading frames (ORFs) bind RNAs, whereas the fourth, encoded by the U L 41 ORF, acts as an RNase (reviewed in reference 44). Apart from potential regulatory functions, interest in the RNA binding proteins stemmed from the observation that virions package mRNAs (40,42). Moreover, in the course of studies of this phenomenon, our laboratories reported that VP22, the product of the U L 49 ORF, transports the mRNA from infected to uninfected cells for expression prior to viral infection (41). The studies reported here were initially designed to determine the contribution of VP22 to the packaging of mRNAs in the virion. We show that a series of ⌬U L 49 mutants derived from independent transfections of viral DNA lacking the U L 49 ORF yielded recombinant viruses defective in the U L 41 gene. On the basis of the results reported in this article and in parallel studies published by Taddeo et al. (52), we conclude that VP22 and VP16 are both required for the replication of viruses encoding functional U L 41 protein. Relevant to this report are the following.The shutoff of cellular protein synthesis, a function designated virion host shutoff (vhs), was first identified and mapped to the U L 41 ORF by Frenkel and colleagues (25,26,47). Intensive studies carried out over 2 decades demonstrated that the U L 41 product is a ␥ 2 protein, that it is packaged in the virion, and that it mediates the degradation of mRNA...

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“…La proteína p53 tiene un peso molecular de 53 kD (de ahí su nombre) y su principal característica es que interviene directamente en el control del ciclo celular y en la replicación y reparación del ácido desoxirribonucleico (ADN), manteniendo la estabilidad genómica, activando la apoptosis y participando en la respuesta celular a agentes externos nocivos. La proteína p53 es fundamentalmente un regulador de la expresión génica, actuando como factor de transcripción capaz de activar o de inhibir genes específicos, entre los que destacan el gen p21, los genes bax y fas, el gen IGF-BP3 (insulin-like growth factor-binding protein-3), el gen gadd45 (growth arrest and DNA damage-45) y el gen de la ciclina G, todos ellos implicados en el ciclo de división celular y por ende en los procesos de proliferación y apoptosis (1,2). De estas mismas funciones deriva el hecho de que la proteína supresora de tumores p53 está relacionada con la prevención de cáncer, debido a su habilidad para regular la transformación, proliferación y muerte celular ante diversos agentes, entre ellos la agresión a los ácidos nucleicos y el estrés oncogénico (1)(2)(3)(4).…”

Section: Introductionunclassified

“…La proteína p53 es fundamentalmente un regulador de la expresión génica, actuando como factor de transcripción capaz de activar o de inhibir genes específicos, entre los que destacan el gen p21, los genes bax y fas, el gen IGF-BP3 (insulin-like growth factor-binding protein-3), el gen gadd45 (growth arrest and DNA damage-45) y el gen de la ciclina G, todos ellos implicados en el ciclo de división celular y por ende en los procesos de proliferación y apoptosis (1,2). De estas mismas funciones deriva el hecho de que la proteína supresora de tumores p53 está relacionada con la prevención de cáncer, debido a su habilidad para regular la transformación, proliferación y muerte celular ante diversos agentes, entre ellos la agresión a los ácidos nucleicos y el estrés oncogénico (1)(2)(3)(4). El gen p53 codifica la proteína p53 y en el genoma humano parecen existir unas 200 copias de este gen, localizadas en el cromosoma 17.…”

Section: Introductionunclassified

Caracterización bioquímica del nervio óptico en el ratón que sobreexpresa el gen P53: Análisis de estrés oxidativo

Gallego-Pinazo

Zanón‐Moreno

Sanz

et al. 2008

Arch Soc Esp Oftalmol

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Poor intercellular transport and absence of enhanced antiproliferative activity after non‐viral gene transfer of VP22‐P53 or P53‐VP22 fusions into p53 null cell lines in vitro or in vivo

Abstract: Our study indicates that a gene transfer strategy using VP22 cannot be considered as a universal system to improve the delivery of any protein.

Cited by 8 publications

References 38 publications

Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer

Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer

Replication-Competent Herpes Simplex Virus 1 Isolates Selected from Cells Transfected with a Bacterial Artificial Chromosome DNA Lacking Only the U _L 49 Gene Vary with Respect to the Defect in the U _L 41 Gene Encoding Host Shutoff RNase

Caracterización bioquímica del nervio óptico en el ratón que sobreexpresa el gen P53: Análisis de estrés oxidativo

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Poor intercellular transport and absence of enhanced antiproliferative activity after non‐viral gene transfer of VP22‐P53 or P53‐VP22 fusions into p53 null cell lines in vitro or in vivo

Abstract: Our study indicates that a gene transfer strategy using VP22 cannot be considered as a universal system to improve the delivery of any protein.

Cited by 8 publications

References 38 publications

Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer

Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer

Replication-Competent Herpes Simplex Virus 1 Isolates Selected from Cells Transfected with a Bacterial Artificial Chromosome DNA Lacking Only the U L 49 Gene Vary with Respect to the Defect in the U L 41 Gene Encoding Host Shutoff RNase

Caracterización bioquímica del nervio óptico en el ratón que sobreexpresa el gen P53: Análisis de estrés oxidativo

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Replication-Competent Herpes Simplex Virus 1 Isolates Selected from Cells Transfected with a Bacterial Artificial Chromosome DNA Lacking Only the U _L 49 Gene Vary with Respect to the Defect in the U _L 41 Gene Encoding Host Shutoff RNase