Initiation of transcription from the minute virus of mice P4 promoter is stimulated in rat cells expressing a c-Ha-ras oncogene

Spegelaere, Pierre; Hille, B van; Spruyt, Nathalie; Faisst, Steffen; Cornelis, Jan J.; Rommelaere, Jean

doi:10.1128/jvi.65.9.4919-4928.1991

Cited by 33 publications

(19 citation statements)

References 47 publications

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“…Wild-type and V393I mutant HNF-4 ␣ proteins were transiently expressed in COS-1 cells. Nuclei were isolated and nuclear extracts were prepared as previously described (21,22). Protein concentration was determined by the Bradford assay (Bio-Rad Laboratories, Richmond, CA) according to the manufacturer's recommendations.…”

Section: Methodsmentioning

confidence: 99%

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Hani¹,

Suaud²,

Boutin³

et al. 1998

J. Clin. Invest.

114

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Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.

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Section: Methodsmentioning

confidence: 99%

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Hani¹,

Suaud²,

Boutin³

et al. 1998

J. Clin. Invest.

114

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“…EBS-dependent activation of promoter P4 by the ras oncogene. Promoter P4 has been shown to be up-modulated in ras-transformed FREJ4 fibroblasts compared with parental FR3T3 cells (54). This promoter activation is likely to contribute to the overproduction of cytotoxic NS-1 proteins as observed in ras (57) and other (51) transformants.…”

Section: Discussionmentioning

confidence: 98%

“…The EBS contributes to ras-mediated activation of promoter P4. The transcriptional activity of promoter P4 is greater in the ras-transformed FREJ4 cell line than in the parental FR3T3 cells (54). Since EBS motifs are involved in the ras-mediated up-modulation of other promoters (11,60,61), the role of the P4 EBS in the activation of promoter P4 by c-Ha-ras was investigated.…”

Section: Vol 70 1996mentioning

confidence: 99%

“…Previous reports have shown that this increase in NS-1 production is controlled, in particular, at the level of initiation of transcription. Indeed, the activity of promoter P4 was found to be up-modulated in the c-Ha-ras-transformed rat fibroblast line FREJ4 (54). Hence, the regulation of this promoter constitutes a key issue for the understanding of parvovirus-host cell interactions and may provide insights into the mechanism(s) by which neoplastic transformation exacerbates the parvoviral lytic effect.…”

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ras oncogene-dependent activation of the P4 promoter of minute virus of mice through a proximal P4 element interacting with the Ets family of transcription factors

Fuks

Deleu

Dinsart

et al. 1996

J Virol

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The P4 promoter of parvovirus minute virus of mice (MVMp) directs transcription of the genes coding for nonstructural proteins. The activity of promoter P4 is regulated by several cis-acting DNA elements. Among these, a promoter-proximal GC box was shown to be essential for P4 activity (J. K. Ahn, B. J. Gavin, G. Kumar, and D. C. Ward, J. Virol. 63:5425-5439, 1989). In this study, a motif homologous to an Ets transcription factor-binding site (EBS), located immediately upstream from the GC box, was found to be required for the full activity of promoter P4 in the ras-transformed rat fibroblast cell line FREJ4. In normal parental FR3T3 cells, the transcriptional function of P4 EBS was insignificant but could be restored by transient cell transfection with the c-Ha-ras oncogene. P4 EBS may thus contribute to the stimulation of promoter P4 in ras-transformed cells. Electrophoretic mobility shift assays using crude extracts from FREJ4 cells revealed the binding of a member(s) of the Ets family of transcription factors to the P4 EBS, as well as the interaction of two members of the Sp1 family, Sp1 and Sp3, with the adjacent GC box. When produced in Drosophila melanogaster SL2 cells,Ets-1 and Sp1 proteins acted synergistically to transactivate promoter P4 through their respective cognate sites.

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“…It is most likely due to differential completion of several further, intracellular steps of the parvoviral life cycle, notably initiation of the synthesis of P4-driven viral transcripts, as previously dem-onstrated in normal versus EJ-ras-transformed rat fibroblasts. 25 We next examined the oncoselectivity of rMVMpmediated gene transduction by infecting the various cell models with a recombinant virus expressing the CAT reporter gene under control of the P38 promoter ( Figure 1). CAT expression ( Figure 2) was substantial in all infected tumor cell types, despite important variations according to the cell type.…”

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2000

Gene Ther

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A recombinant MVMp of the fibrotropic strain of minute virus of mice (MVMp) expressing the chloramphenicol acetyltransferase reporter gene was used to infect a series of biologically relevant cultured cells, normal or tumor-derived, including normal melanocytes versus melanoma cells, normal mammary epithelial cells versus breast adenocarcinoma cells, and normal neurons or astrocytes versus glioma cells. As a reference cell system we used normal human fibroblasts versus the SV40-transformed fibroblast cell line NB324K. After infection, we observed good expression of the reporter gene in the different tumor cell types, but only poor expression if any in the corresponding normal cells. We also constructed a recombinant MVMp expressing the green fluorescent protein reporter gene and assessed by flow cytometry the efficiency of gene transduction into the different target cells. At a multiplicity of infection of 30, we observed substantial transduction of the gene into most of the tumor cell types tested, but only marginal transduction into normal cells under the same experimental conditions. Finally, we demonstrated that a recombinant MVMp expressing the herpes simplex virus thymidine kinase gene can, in vitro, cause efficient killing of most tumor cell types in the presence of ganciclovir, whilst affecting normal proliferating cells only marginally if at all. However, in the same experimental condition, breast tumor cells appeared to be resistant to GCV-mediated cytotoxicity, possibly because these cells are not susceptible to the bystander effect. Our data suggest that MVMp-based vectors could prove useful as selective vehicles for anticancer gene therapy, particularly for in vivo delivery of cytotoxic effector genes into tumor cells.

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Initiation of transcription from the minute virus of mice P4 promoter is stimulated in rat cells expressing a c-Ha-ras oncogene

Cited by 33 publications

References 47 publications

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

ras oncogene-dependent activation of the P4 promoter of minute virus of mice through a proximal P4 element interacting with the Ets family of transcription factors

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