Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds

Chemical inhibitors of cyclin-dependent kinase (CDK), like roscovitine, are promising drugs in thecontext of new cancer therapies. Roscovitine and related compounds, like seliciclib and olomoucine, are effective inducers of apoptosis in many proliferating cells in culture. These compounds are known...

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Detalhes bibliográficos
Autores: Garrofé Ochoa, Xènia, Cosialls, Ana M, Ribas i Fortuny, Judit, Gil, Joan, Boix Torras, Jacint
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2011
País:España
Recursos:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/48085
Acesso em linha:https://doi.org/10.1007/s10495-011-0603-3
http://hdl.handle.net/10459.1/48085
Access Level:acceso abierto
Palavra-chave:Bcl-2
CDK
Roscovitine
Olomoucine
Apoptosis
Apoptosi
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spelling Trancriptional modulation of apoptotis regulators by Roscovitine and related compoundsGarrofé Ochoa, XèniaCosialls, Ana MRibas i Fortuny, JuditGil, JoanBoix Torras, JacintBcl-2CDKRoscovitineOlomoucineApoptosisApoptosiApoptosisChemical inhibitors of cyclin-dependent kinase (CDK), like roscovitine, are promising drugs in thecontext of new cancer therapies. Roscovitine and related compounds, like seliciclib and olomoucine, are effective inducers of apoptosis in many proliferating cells in culture. These compounds are known to activate the intrinsic or mitochondrial pathway of apoptosis. In order to better characterize this intrinsic pathway, a transcriptional analysis was performed using the reverse transcriptase-multiplex ligation-dependent probe amplification procedure (RT-MLPA). In five cell lines, we detected an early and marked reduction of most transcripts, which is consistent with the disruption of transcription that results from the inhibition of CDK7 and CDK9. However, the mRNA of p53-upregulated modulator of apoptosis (PUMA) gene escaped from this transcription inhibition in neuroblastoma cells with a functional p53 protein. The increase of PUMA mRNA was not found in roscovitine-treated cell lines defective in p53, which underwent apoptosis like their p53 proficient counterparts. In addition, in SH-SY5Y cells, sublethal and lethal concentrations of roscovitine produced equivalent increases of PUMA mRNA and protein. In conclusion, the increased expression of PUMA was not associated with apoptosis induction. On the contrary, mRNA and protein depletion of MCL-1 gene correlated the best with cell demise. Moreover, NOXA protein suffered a far minor decrease than MCL-1. Because of the selective neutr alization of NOXA by MCL-1, we hypothesize that the disruption of this balance is a critical event in apoptosis induction by roscovitine and related compounds.Springer Science Business Media2011info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://doi.org/10.1007/s10495-011-0603-3http://hdl.handle.net/10459.1/48085reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésVersió postprint del document publicat a: https://doi.org/10.1007/s10495-011-0603-3Apoptosis, 2011, vol. 16, num. 7, p. 660-670(c) Springer Science Business Media, 2011info:eu-repo/semantics/openAccessoai:repositori.udl.cat:10459.1/480852026-06-24T12:42:17Z
dc.title.none.fl_str_mv Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds
title Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds
spellingShingle Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds
Garrofé Ochoa, Xènia
Bcl-2
CDK
Roscovitine
Olomoucine
Apoptosis
Apoptosi
Apoptosis
title_short Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds
title_full Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds
title_fullStr Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds
title_full_unstemmed Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds
title_sort Trancriptional modulation of apoptotis regulators by Roscovitine and related compounds
dc.creator.none.fl_str_mv Garrofé Ochoa, Xènia
Cosialls, Ana M
Ribas i Fortuny, Judit
Gil, Joan
Boix Torras, Jacint
author Garrofé Ochoa, Xènia
author_facet Garrofé Ochoa, Xènia
Cosialls, Ana M
Ribas i Fortuny, Judit
Gil, Joan
Boix Torras, Jacint
author_role author
author2 Cosialls, Ana M
Ribas i Fortuny, Judit
Gil, Joan
Boix Torras, Jacint
author2_role author
author
author
author
dc.subject.none.fl_str_mv Bcl-2
CDK
Roscovitine
Olomoucine
Apoptosis
Apoptosi
Apoptosis
topic Bcl-2
CDK
Roscovitine
Olomoucine
Apoptosis
Apoptosi
Apoptosis
description Chemical inhibitors of cyclin-dependent kinase (CDK), like roscovitine, are promising drugs in thecontext of new cancer therapies. Roscovitine and related compounds, like seliciclib and olomoucine, are effective inducers of apoptosis in many proliferating cells in culture. These compounds are known to activate the intrinsic or mitochondrial pathway of apoptosis. In order to better characterize this intrinsic pathway, a transcriptional analysis was performed using the reverse transcriptase-multiplex ligation-dependent probe amplification procedure (RT-MLPA). In five cell lines, we detected an early and marked reduction of most transcripts, which is consistent with the disruption of transcription that results from the inhibition of CDK7 and CDK9. However, the mRNA of p53-upregulated modulator of apoptosis (PUMA) gene escaped from this transcription inhibition in neuroblastoma cells with a functional p53 protein. The increase of PUMA mRNA was not found in roscovitine-treated cell lines defective in p53, which underwent apoptosis like their p53 proficient counterparts. In addition, in SH-SY5Y cells, sublethal and lethal concentrations of roscovitine produced equivalent increases of PUMA mRNA and protein. In conclusion, the increased expression of PUMA was not associated with apoptosis induction. On the contrary, mRNA and protein depletion of MCL-1 gene correlated the best with cell demise. Moreover, NOXA protein suffered a far minor decrease than MCL-1. Because of the selective neutr alization of NOXA by MCL-1, we hypothesize that the disruption of this balance is a critical event in apoptosis induction by roscovitine and related compounds.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1007/s10495-011-0603-3
http://hdl.handle.net/10459.1/48085
url https://doi.org/10.1007/s10495-011-0603-3
http://hdl.handle.net/10459.1/48085
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1007/s10495-011-0603-3
Apoptosis, 2011, vol. 16, num. 7, p. 660-670
dc.rights.none.fl_str_mv (c) Springer Science Business Media, 2011
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Springer Science Business Media, 2011
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Science Business Media
publisher.none.fl_str_mv Springer Science Business Media
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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