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Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport
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| Zeitschriftentitel: | Journal of Virology |
|---|---|
| Personen und Körperschaften: | , , , , , |
| In: | Journal of Virology, 84, 2010, 4, S. 2090-2099 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
|
| Schlagwörter: |
| author_facet |
Riolobos, Laura Valle, Noelia Hernando, Eva Maroto, Beatriz Kann, Michael Almendral, José M. Riolobos, Laura Valle, Noelia Hernando, Eva Maroto, Beatriz Kann, Michael Almendral, José M. |
|---|---|
| author |
Riolobos, Laura Valle, Noelia Hernando, Eva Maroto, Beatriz Kann, Michael Almendral, José M. |
| spellingShingle |
Riolobos, Laura Valle, Noelia Hernando, Eva Maroto, Beatriz Kann, Michael Almendral, José M. Journal of Virology Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport Virology Insect Science Immunology Microbiology |
| author_sort |
riolobos, laura |
| spelling |
Riolobos, Laura Valle, Noelia Hernando, Eva Maroto, Beatriz Kann, Michael Almendral, José M. 0022-538X 1098-5514 American Society for Microbiology Virology Insect Science Immunology Microbiology http://dx.doi.org/10.1128/jvi.01550-09 <jats:title>ABSTRACT</jats:title> <jats:p> The central role of Raf protein kinase isoforms in human cancer demands specific anti-Raf therapeutic inhibitors. Parvoviruses are currently used in experimental cancer therapy due to their natural oncotropism and lytic life cycle. In searching for mechanisms underlying parvovirus oncolysis, we found that trimers of the major structural protein (VP) of the parvovirus minute virus of mice (MVM), which have to be imported into the nucleus for capsid assembly, undergo phosphorylation by the Raf-1 kinase. Purified Raf-1 phosphorylated the capsid subunits <jats:italic>in vitro</jats:italic> to the two-dimensional pattern found in natural MVM infections. VP trimers isolated from mammalian cells translocated into the nucleus of digitonin-permeabilized human cells. In contrast, VP trimers isolated from insect cells, which are devoid of Raf-1, were neither phosphorylated nor imported into the mammalian nucleus. However, the coexpression of a constitutively active Raf-1 kinase in insect cells restored VP trimer phosphorylation and nuclear transport competence. In MVM-infected normal and transformed cells, Raf-1 inhibition resulted in cytoplasmic retention of capsid proteins, preventing their nuclear assembly and progeny virus maturation. The level of Raf-1 activity in cancer cells was consistent with the extent of VP specific phosphorylation and with the permissiveness to MVM infection. Thus, Raf-1 control of nuclear translocation of MVM capsid assembly intermediates provides a novel target for viral oncolysis. MVM may reinforce specific therapies against frequent human cancers with deregulated Raf signaling. </jats:p> Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport Journal of Virology |
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| title |
Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_unstemmed |
Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_full |
Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_fullStr |
Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_full_unstemmed |
Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_short |
Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_sort |
viral oncolysis that targets raf-1 signaling control of nuclear transport |
| topic |
Virology Insect Science Immunology Microbiology |
| url |
http://dx.doi.org/10.1128/jvi.01550-09 |
| publishDate |
2010 |
| physical |
2090-2099 |
| description |
<jats:title>ABSTRACT</jats:title>
<jats:p>
The central role of Raf protein kinase isoforms in human cancer demands specific anti-Raf therapeutic inhibitors. Parvoviruses are currently used in experimental cancer therapy due to their natural oncotropism and lytic life cycle. In searching for mechanisms underlying parvovirus oncolysis, we found that trimers of the major structural protein (VP) of the parvovirus minute virus of mice (MVM), which have to be imported into the nucleus for capsid assembly, undergo phosphorylation by the Raf-1 kinase. Purified Raf-1 phosphorylated the capsid subunits
<jats:italic>in vitro</jats:italic>
to the two-dimensional pattern found in natural MVM infections. VP trimers isolated from mammalian cells translocated into the nucleus of digitonin-permeabilized human cells. In contrast, VP trimers isolated from insect cells, which are devoid of Raf-1, were neither phosphorylated nor imported into the mammalian nucleus. However, the coexpression of a constitutively active Raf-1 kinase in insect cells restored VP trimer phosphorylation and nuclear transport competence. In MVM-infected normal and transformed cells, Raf-1 inhibition resulted in cytoplasmic retention of capsid proteins, preventing their nuclear assembly and progeny virus maturation. The level of Raf-1 activity in cancer cells was consistent with the extent of VP specific phosphorylation and with the permissiveness to MVM infection. Thus, Raf-1 control of nuclear translocation of MVM capsid assembly intermediates provides a novel target for viral oncolysis. MVM may reinforce specific therapies against frequent human cancers with deregulated Raf signaling.
</jats:p> |
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| author | Riolobos, Laura, Valle, Noelia, Hernando, Eva, Maroto, Beatriz, Kann, Michael, Almendral, José M. |
| author_facet | Riolobos, Laura, Valle, Noelia, Hernando, Eva, Maroto, Beatriz, Kann, Michael, Almendral, José M., Riolobos, Laura, Valle, Noelia, Hernando, Eva, Maroto, Beatriz, Kann, Michael, Almendral, José M. |
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| description | <jats:title>ABSTRACT</jats:title> <jats:p> The central role of Raf protein kinase isoforms in human cancer demands specific anti-Raf therapeutic inhibitors. Parvoviruses are currently used in experimental cancer therapy due to their natural oncotropism and lytic life cycle. In searching for mechanisms underlying parvovirus oncolysis, we found that trimers of the major structural protein (VP) of the parvovirus minute virus of mice (MVM), which have to be imported into the nucleus for capsid assembly, undergo phosphorylation by the Raf-1 kinase. Purified Raf-1 phosphorylated the capsid subunits <jats:italic>in vitro</jats:italic> to the two-dimensional pattern found in natural MVM infections. VP trimers isolated from mammalian cells translocated into the nucleus of digitonin-permeabilized human cells. In contrast, VP trimers isolated from insect cells, which are devoid of Raf-1, were neither phosphorylated nor imported into the mammalian nucleus. However, the coexpression of a constitutively active Raf-1 kinase in insect cells restored VP trimer phosphorylation and nuclear transport competence. In MVM-infected normal and transformed cells, Raf-1 inhibition resulted in cytoplasmic retention of capsid proteins, preventing their nuclear assembly and progeny virus maturation. The level of Raf-1 activity in cancer cells was consistent with the extent of VP specific phosphorylation and with the permissiveness to MVM infection. Thus, Raf-1 control of nuclear translocation of MVM capsid assembly intermediates provides a novel target for viral oncolysis. MVM may reinforce specific therapies against frequent human cancers with deregulated Raf signaling. </jats:p> |
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| spelling | Riolobos, Laura Valle, Noelia Hernando, Eva Maroto, Beatriz Kann, Michael Almendral, José M. 0022-538X 1098-5514 American Society for Microbiology Virology Insect Science Immunology Microbiology http://dx.doi.org/10.1128/jvi.01550-09 <jats:title>ABSTRACT</jats:title> <jats:p> The central role of Raf protein kinase isoforms in human cancer demands specific anti-Raf therapeutic inhibitors. Parvoviruses are currently used in experimental cancer therapy due to their natural oncotropism and lytic life cycle. In searching for mechanisms underlying parvovirus oncolysis, we found that trimers of the major structural protein (VP) of the parvovirus minute virus of mice (MVM), which have to be imported into the nucleus for capsid assembly, undergo phosphorylation by the Raf-1 kinase. Purified Raf-1 phosphorylated the capsid subunits <jats:italic>in vitro</jats:italic> to the two-dimensional pattern found in natural MVM infections. VP trimers isolated from mammalian cells translocated into the nucleus of digitonin-permeabilized human cells. In contrast, VP trimers isolated from insect cells, which are devoid of Raf-1, were neither phosphorylated nor imported into the mammalian nucleus. However, the coexpression of a constitutively active Raf-1 kinase in insect cells restored VP trimer phosphorylation and nuclear transport competence. In MVM-infected normal and transformed cells, Raf-1 inhibition resulted in cytoplasmic retention of capsid proteins, preventing their nuclear assembly and progeny virus maturation. The level of Raf-1 activity in cancer cells was consistent with the extent of VP specific phosphorylation and with the permissiveness to MVM infection. Thus, Raf-1 control of nuclear translocation of MVM capsid assembly intermediates provides a novel target for viral oncolysis. MVM may reinforce specific therapies against frequent human cancers with deregulated Raf signaling. </jats:p> Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport Journal of Virology |
| spellingShingle | Riolobos, Laura, Valle, Noelia, Hernando, Eva, Maroto, Beatriz, Kann, Michael, Almendral, José M., Journal of Virology, Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport, Virology, Insect Science, Immunology, Microbiology |
| title | Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_full | Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_fullStr | Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_full_unstemmed | Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_short | Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| title_sort | viral oncolysis that targets raf-1 signaling control of nuclear transport |
| title_unstemmed | Viral Oncolysis That Targets Raf-1 Signaling Control of Nuclear Transport |
| topic | Virology, Insect Science, Immunology, Microbiology |
| url | http://dx.doi.org/10.1128/jvi.01550-09 |