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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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Fusogenic exosomes are associated with MPMV. (A) MPMV Env, Gag, and exosomal CD9, CD81, and MHCI were detected by immunoblotting in P70 (see Materials and methods). (B) CD81 is detected on the surface and p27Ca Gag of MPMV inside of exosomes by immuno-EM (see Materials and methods). The inset is an enlargement of the particle indicated by the arrow. (C) MPMV Env and p27 capsid are associated with exosomal markers CD81 and -63. P70 preparation was incubated with or without biotinylated anti-human CD81 antibody and fractionated in a capture assay using magnetic streptavidin microbeads (see Materials and methods). The unbound fraction (FT), the final wash, and the bound fraction (eluate) were analyzed by immunoblotting. Antibodies to CD63 and -81 were used together for convenience because both identify distinct polypeptides. The experiments in A and B were done multiple times and the experiment in C twice.
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fig4: Fusogenic exosomes are associated with MPMV. (A) MPMV Env, Gag, and exosomal CD9, CD81, and MHCI were detected by immunoblotting in P70 (see Materials and methods). (B) CD81 is detected on the surface and p27Ca Gag of MPMV inside of exosomes by immuno-EM (see Materials and methods). The inset is an enlargement of the particle indicated by the arrow. (C) MPMV Env and p27 capsid are associated with exosomal markers CD81 and -63. P70 preparation was incubated with or without biotinylated anti-human CD81 antibody and fractionated in a capture assay using magnetic streptavidin microbeads (see Materials and methods). The unbound fraction (FT), the final wash, and the bound fraction (eluate) were analyzed by immunoblotting. Antibodies to CD63 and -81 were used together for convenience because both identify distinct polypeptides. The experiments in A and B were done multiple times and the experiment in C twice.

Mentions: Several observations supported this possibility. The genome of IEH but not that of I0 cells contained MPMV sequences (unpublished data). The P70 from IEH but not from I0 cells had reverse transcriptase activity (Fig. 3 B, inset). Also, I0 cells became fusogenic (Fig. S1, A and C, available at http://www.jcb.org/cgi/content/full/jcb.200507069/DC1) and acquired expression of MPMV p27CA after incubation with P70 from either IEH or CMMT, which is the prototypical cell line that produces MPMV (for review see Fine and Schochetman, 1978; Fig. S1 B and not depicted). Immunoblotting confirmed that P70 of IEH cells contained the exosomal proteins CD9, CD81, and major histocompatibility complex class I (MHCI; Thery et al., 1999) and the MPMV proteins gp20 Env and the capsid p27CA Gag (Fig. 4 A). Nearly all particles in P70 from IEH cells contained the MPMV capsid protein p27CA (Fig. 4 B) in its mature form (Fig. 4 A), indicating that nearly all observed vesicles contained MPMV.


A primate virus generates transformed human cells by fusion.

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

Fusogenic exosomes are associated with MPMV. (A) MPMV Env, Gag, and exosomal CD9, CD81, and MHCI were detected by immunoblotting in P70 (see Materials and methods). (B) CD81 is detected on the surface and p27Ca Gag of MPMV inside of exosomes by immuno-EM (see Materials and methods). The inset is an enlargement of the particle indicated by the arrow. (C) MPMV Env and p27 capsid are associated with exosomal markers CD81 and -63. P70 preparation was incubated with or without biotinylated anti-human CD81 antibody and fractionated in a capture assay using magnetic streptavidin microbeads (see Materials and methods). The unbound fraction (FT), the final wash, and the bound fraction (eluate) were analyzed by immunoblotting. Antibodies to CD63 and -81 were used together for convenience because both identify distinct polypeptides. The experiments in A and B were done multiple times and the experiment in C twice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171256&req=5

fig4: Fusogenic exosomes are associated with MPMV. (A) MPMV Env, Gag, and exosomal CD9, CD81, and MHCI were detected by immunoblotting in P70 (see Materials and methods). (B) CD81 is detected on the surface and p27Ca Gag of MPMV inside of exosomes by immuno-EM (see Materials and methods). The inset is an enlargement of the particle indicated by the arrow. (C) MPMV Env and p27 capsid are associated with exosomal markers CD81 and -63. P70 preparation was incubated with or without biotinylated anti-human CD81 antibody and fractionated in a capture assay using magnetic streptavidin microbeads (see Materials and methods). The unbound fraction (FT), the final wash, and the bound fraction (eluate) were analyzed by immunoblotting. Antibodies to CD63 and -81 were used together for convenience because both identify distinct polypeptides. The experiments in A and B were done multiple times and the experiment in C twice.
Mentions: Several observations supported this possibility. The genome of IEH but not that of I0 cells contained MPMV sequences (unpublished data). The P70 from IEH but not from I0 cells had reverse transcriptase activity (Fig. 3 B, inset). Also, I0 cells became fusogenic (Fig. S1, A and C, available at http://www.jcb.org/cgi/content/full/jcb.200507069/DC1) and acquired expression of MPMV p27CA after incubation with P70 from either IEH or CMMT, which is the prototypical cell line that produces MPMV (for review see Fine and Schochetman, 1978; Fig. S1 B and not depicted). Immunoblotting confirmed that P70 of IEH cells contained the exosomal proteins CD9, CD81, and major histocompatibility complex class I (MHCI; Thery et al., 1999) and the MPMV proteins gp20 Env and the capsid p27CA Gag (Fig. 4 A). Nearly all particles in P70 from IEH cells contained the MPMV capsid protein p27CA (Fig. 4 B) in its mature form (Fig. 4 A), indicating that nearly all observed vesicles contained MPMV.

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