Down-regulation of the human c-fos and c-myc proto-oncogene promoters by adeno-associated virus Rep78

doi:10.1016/0304-3835(94)90193-7

Cancer Letters

Volume 81, Issue 2, 30 June 1994, Pages 129-136

https://doi.org/10.1016/0304-3835(94)90193-7 Get rights and content

Abstract

Adeno-associated virus (AAV) is a non-pathogenic human parvovirus which has anti-tumor and anti-proliferation properties in tissue culture and animal studies. Furthermore, AAV infection is negatively associated with human cervical cancer. C-myc has been implicated in cervical cancer, and c-fos is involved in signal transduction initiation of cell growth. To study the potential regulation of these two prominent human proto-oncogenes by AAV, the expression of three marker coding sequences ligated 3′ of the proto-oncogene promoters were observed. Demonstrated here, the AAV Rep78 gene product was able to down-regulate the human c-fos and c-myc proto-oncogene promoters in all three assay systems. These interactions may partially explain AAVs anti-proliferation properties.

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In this context, given that recombination between AAV genomes appears to be a surprisingly common event in primate tissue18 and the number of vector genomes delivered to the primate liver in these experiments was relatively low, it is possible that recombination occurred between preexisting integrated or persistent nonintegrated AAV genomes in the liver and the incoming AAV8-αgal genome, resulting in recombinants with reduced αgal expression. Finally, given that low level AAV rep expression is required to maintain vector persistence in infected cells,21 and Rep protein is known to suppress expression,28,29,30 it is possible that hepatic expression of AAV8-αgal in NHPs was suppressed by the expression of rep from previous AAV infection(s). This is plausible as the inclusion of Rep binding sites is a requirement for vector packaging.
Liver-directed gene therapy with adeno-associated virus (AAV) vectors effectively treats mouse models of lysosomal storage diseases (LSDs). We asked whether these results were likely to translate to patients. To understand to what extent preexisting anti-AAV8 antibodies could impede AAV8-mediated liver transduction in primates, commonly preexposed to AAV, we quantified the effects of preexisting antibodies on liver transduction and subsequent transgene expression in mouse and nonhuman primate (NHP) models. Using the highest viral dose previously reported in a clinical trial, passive transfer of NHP sera containing relatively low anti-AAV8 titers into mice blocked liver transduction, which could be partially overcome by increasing vector dose tenfold. Based on this and a survey of anti-AAV8 titers in 112 humans, we predict that high-dose systemic gene therapy would successfully transduce liver in >50% of human patients. However, although high-dose AAV8 administration to mice and monkeys with equivalent anti-AAV8 titers led to comparable liver vector copy numbers, the resulting transgene expression in primates was ~1.5-logs lower than mice. This suggests vector fate differs in these species and that strategies focused solely on overcoming preexisting vector-specific antibodies may be insufficient to achieve clinically meaningful expression levels of LSD genes using a liver-directed gene therapy approach in patients.
Identification of a cytoplasmic interaction partner of the large regulatory proteins Rep78/Rep68 of adeno-associated virus type 2 (AAV-2)
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Since regulation of AAV gene expression in the presence of helpervirus is subject to complex regulatory mechanisms in the nucleus and probably also in the cytoplasm, we turned to a regulatory effect of the large Rep proteins on heterologous gene expression assumed to be primarily exerted in the nucleus. The large Rep proteins have been shown to inhibit several cellular and viral promoters (Antoni et al., 1991; Hermonat, 1994; Horer et al., 1995; Labow et al., 1987) including the long terminal repeat region of the human immunodeficiency virus type 1 (HIV-LTR). Reporter assays with the β-globin gene, which generates a very stable messenger, suggested that the inhibition of the HIV-LTR takes place at the transcriptional level (Horer et al., 1995).
Through yeast two-hybrid analysis and coimmunoprecipitation studies, we have identified a novel cellular AAV-2 Rep78/Rep68 interaction partner located predominantly in the cytoplasm. In public databases, it has been assigned as KCTD5, because of a region of high similarity to the cytoplasmic tetramerization domain of voltage-gated potassium channels. Whereas Rep/KCTD5 interaction relied on the region surrounding the Rep nuclear localization signal, nuclear accumulation of Rep was not required. Wildtype Rep78/Rep68 proteins induced the translocation of large portions of KCTD5 into the nucleus pointing to functional interactions both in the cytoplasm and the nucleus. In line with an anticipated functional interference in the cytoplasm, KCTD5 overexpression completely abrogated Rep68-mediated posttranscriptional activation of a HIV-LTR driven luciferase reporter gene. Our study expands the panel of already identified nuclear Rep interaction partners to a cytoplasmic protein, which raises the awareness that important steps in the AAV life cycle may be regulated in this compartment.
The adeno-associated virus major regulatory protein Rep78-c-Jun-DNA motif complex modulates AP-1 activity
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Multiple epidemiologic studies show that adeno-associated virus (AAV) is negatively associated with cervical cancer (CX CA), a cancer which is positively associated with human papillomavirus (HPV) infection. Mechanisms for this correlation may be by Rep78's (AAV's major regulatory protein) ability to bind the HPV-16 p97 promoter DNA and inhibit transcription, to bind and interfere with the functions of the E7 oncoprotein of HPV-16, and to bind a variety of HPV-important cellular transcription factors such as Sp1 and TBP. c-Jun is another important cellular factor intimately linked to the HPV life cycle, as well as keratinocyte differentiation and skin development. Skin is the natural host tissue for both HPV and AAV. In this article it is demonstrated that Rep78 directly interacts with c-Jun, both in vitro and in vivo, as analyzed by Western blot, yeast two-hybrid cDNA, and electrophoretic mobility shift-supershift assay (EMSA supershift). Addition of anti-Rep78 antibodies inhibited the EMSA supershift. Investigating the biological implications of this interaction, Rep78 inhibited the c-Jun-dependent c-jun promoter in transient and stable chloramphenicol acetyl-transferase (CAT) assays. Rep78 also inhibited c-Jun-augmented c-jun promoter as well as the HPV-16 p97 promoter activity (also c-Jun regulated) in in vitro transcription assays in T47D nuclear extracts. Finally, the Rep78–c-Jun interaction mapped to the amino-half of Rep78. The ability of Rep78 to interact with c-Jun and down-regulate AP-1-dependent transcription suggests one more mechanism by which AAV may modulate the HPV life cycle and the carcinogenesis process.
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Protective roles of adenoassociated virus (AAV) 2 in cervical tumorigenesis are controversial. In an effort to clarify this issue, we tested prevalence of AAV 2 and human papillomavirus (HPV) infection in cervical lesions and adjacent normal tissues.
Tissues of cervical intraepithelial neoplasm (CIN) I (20 patients), CIN II (24 patients), CIN III (25 patients), and invasive cancer (23 patients) were investigated by microdissection and PCR using HPV-16-, HVP-18-, and AAV-2-specific primers.
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Down-regulation of the human c-fos and c-myc proto-oncogene promoters by adeno-associated virus Rep78

Abstract

Virology

Am. J. Obstet. Gynecol.

Virology

Virology

Virology

Lancet

Cell

Biochim. Biophys. Acta

J. Mol. Biol.

Virology

Modification of some biological properties of HeLa cells containing adeno-associated virus DNA integrated into chromosome 17

J. Virol.

Influence of adeno-associated virus on adherence and growth properties of normal cells

J. Virol.

Induction of differentiation-associated changes in established human cells by infection with adeno-associated virus type 2

J. Virol.

Inhibition of adenovirus 12 oncogenicity by adeno-associated virus

Studies on the relationship between adeno-associated virus type 1 and adenoviruses. I. Replication of AAV-1 in certain cell cultures and its effect on helper adenovirus

Virology

Effect of adeno-associated virus on cancer expression by herpesvirus-transformed hamster cells

J. Natl. Cancer Inst.

Interactions of adeno-associated virus with cells transformed by herpes simplex virus

Effect of adeno-associated virus on c-H-ras transformation of NIH 3T3 cells and on tumorigenicity of an NIH 3T3 transformed cell line

Cancer Res.