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A primate virus generates transformed human cells by fusion.

Duelli DM, Hearn S, Myers MP, Lazebnik Y - J. Cell Biol. (2005)

Bottom Line: Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability.We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die.Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

View Article: PubMed Central - PubMed

Affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

ABSTRACT
Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability. The prevailing view is that these events are mutations that affect chromosome segregation or stability. However, genomic and epigenetic variability is also triggered by cell fusion, which is often caused by viruses. Yet, cells fused by viruses are considered harmless because they die. We provide evidence that a primate virus uses both viral and exosomal proteins involved in cell fusion to produce transformed proliferating human cells. Although normal cells indeed fail to proliferate after fusion, expression of an oncogene or a mutated tumor suppressor p53 in just one of the fusion partners is sufficient to produce heterogeneous progeny. We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die. Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

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Antibodies to tetraspanins CD9 and -81 inhibit fusion by MPMVE. (A) Aliquots of MPMVE were incubated with indicated antibodies, washed, and analyzed by immunoblotting (see Materials and methods). (B) Exosomes were treated with indicated antibodies and tested in the fusion assay with I0 or HepG2 cells, which express no CD81 (C). The experiments were done three times with I0 cells, except that total mouse IgG was used as a control only in two of these experiments, and the experiments with HepG2 cells were done twice. ND, not done. The error bars indicate SD. (C) CD81 is transferred to HepG2 cells by MPMVE. HepG2 cells cultured for 22 h without (left) or with (right) MPMVE from IEH cells were probed with an antibody to CD81 (red). The nuclei were visualized with Hoechst 33342 (blue).
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fig5: Antibodies to tetraspanins CD9 and -81 inhibit fusion by MPMVE. (A) Aliquots of MPMVE were incubated with indicated antibodies, washed, and analyzed by immunoblotting (see Materials and methods). (B) Exosomes were treated with indicated antibodies and tested in the fusion assay with I0 or HepG2 cells, which express no CD81 (C). The experiments were done three times with I0 cells, except that total mouse IgG was used as a control only in two of these experiments, and the experiments with HepG2 cells were done twice. ND, not done. The error bars indicate SD. (C) CD81 is transferred to HepG2 cells by MPMVE. HepG2 cells cultured for 22 h without (left) or with (right) MPMVE from IEH cells were probed with an antibody to CD81 (red). The nuclei were visualized with Hoechst 33342 (blue).

Mentions: MPMVE contained two sets of proteins implicated in fusion, the MPMV Env and the cellular tetraspanins CD81 and -9, which modulate fusion by a poorly understood mechanism. To test whether tetraspanins are involved in cell fusion induced by MPMVE, we used the observation that antibodies to CD9 and -81 prevent fusion of mouse gametes and myoblasts (Hemler, 2003). We incubated aliquots of MPMVE with antibodies to CD9, CD81, the capsid p27CA, or the MPMV Env gp20/22. To exclude unspecific effects of antibodies, we used total mouse IgG and an antibody to MHCI, an abundant exosome surface protein (Clayton et al., 2001) that has not been linked to fusion (Fig. 4 C and Fig. 5 A). Antibodies to Env, CD9, and CD81, but not to the capsid protein p27CA, did bind MPMVE (Fig. 5 A), confirming that Env and the tetraspanins were on the surface of MPMVE and that the envelope of MPMVE was intact. After washing away the unbound antibodies, we tested whether the treated MPMVE still fused I0 cells.


A primate virus generates transformed human cells by fusion.

Duelli DM, Hearn S, Myers MP, Lazebnik Y - J. Cell Biol. (2005)

Antibodies to tetraspanins CD9 and -81 inhibit fusion by MPMVE. (A) Aliquots of MPMVE were incubated with indicated antibodies, washed, and analyzed by immunoblotting (see Materials and methods). (B) Exosomes were treated with indicated antibodies and tested in the fusion assay with I0 or HepG2 cells, which express no CD81 (C). The experiments were done three times with I0 cells, except that total mouse IgG was used as a control only in two of these experiments, and the experiments with HepG2 cells were done twice. ND, not done. The error bars indicate SD. (C) CD81 is transferred to HepG2 cells by MPMVE. HepG2 cells cultured for 22 h without (left) or with (right) MPMVE from IEH cells were probed with an antibody to CD81 (red). The nuclei were visualized with Hoechst 33342 (blue).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171256&req=5

fig5: Antibodies to tetraspanins CD9 and -81 inhibit fusion by MPMVE. (A) Aliquots of MPMVE were incubated with indicated antibodies, washed, and analyzed by immunoblotting (see Materials and methods). (B) Exosomes were treated with indicated antibodies and tested in the fusion assay with I0 or HepG2 cells, which express no CD81 (C). The experiments were done three times with I0 cells, except that total mouse IgG was used as a control only in two of these experiments, and the experiments with HepG2 cells were done twice. ND, not done. The error bars indicate SD. (C) CD81 is transferred to HepG2 cells by MPMVE. HepG2 cells cultured for 22 h without (left) or with (right) MPMVE from IEH cells were probed with an antibody to CD81 (red). The nuclei were visualized with Hoechst 33342 (blue).
Mentions: MPMVE contained two sets of proteins implicated in fusion, the MPMV Env and the cellular tetraspanins CD81 and -9, which modulate fusion by a poorly understood mechanism. To test whether tetraspanins are involved in cell fusion induced by MPMVE, we used the observation that antibodies to CD9 and -81 prevent fusion of mouse gametes and myoblasts (Hemler, 2003). We incubated aliquots of MPMVE with antibodies to CD9, CD81, the capsid p27CA, or the MPMV Env gp20/22. To exclude unspecific effects of antibodies, we used total mouse IgG and an antibody to MHCI, an abundant exosome surface protein (Clayton et al., 2001) that has not been linked to fusion (Fig. 4 C and Fig. 5 A). Antibodies to Env, CD9, and CD81, but not to the capsid protein p27CA, did bind MPMVE (Fig. 5 A), confirming that Env and the tetraspanins were on the surface of MPMVE and that the envelope of MPMVE was intact. After washing away the unbound antibodies, we tested whether the treated MPMVE still fused I0 cells.

Bottom Line: Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability.We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die.Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

View Article: PubMed Central - PubMed

Affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

ABSTRACT
Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability. The prevailing view is that these events are mutations that affect chromosome segregation or stability. However, genomic and epigenetic variability is also triggered by cell fusion, which is often caused by viruses. Yet, cells fused by viruses are considered harmless because they die. We provide evidence that a primate virus uses both viral and exosomal proteins involved in cell fusion to produce transformed proliferating human cells. Although normal cells indeed fail to proliferate after fusion, expression of an oncogene or a mutated tumor suppressor p53 in just one of the fusion partners is sufficient to produce heterogeneous progeny. We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die. Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

Show MeSH
Related in: MedlinePlus