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dc.contributor.author
Zaldua, Natalia
dc.contributor.author
LLavero, Francisco
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Artaso, Alain
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Gálvez, Patricia
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Lacerda, Hadriano M.
dc.contributor.author
Parada, Luis Antonio
dc.contributor.author
Zugaza, José L.
dc.date.available
2017-12-07T15:32:17Z
dc.date.issued
2016-02
dc.identifier.citation
Zaldua, Natalia; LLavero, Francisco; Artaso, Alain; Gálvez, Patricia; Lacerda, Hadriano M.; et al.; Rac1/p21-activated kinase pathway controls retinoblastoma protein phosphorylation and E2F transcription factor activation in B lymphocytes; Wiley; Febs Journal; 283; 4; 2-2016; 647-661
dc.identifier.issn
1742-464X
dc.identifier.uri
http://hdl.handle.net/11336/29940
dc.description.abstract
Small GTPases of the Ras superfamily are capable of activating E2F-dependent transcription leading to cell proliferation, but the molecular mechanisms are poorly understood. In this study, using immortalized chicken DT40 B cell lines to investigate the role of the Vav/Rac signalling cascade on B cell proliferation, it is shown that the proliferative response triggered by B cell receptor activation is dramatically reduced in the absence of Vav3 expression. Analysis of this proliferative defect shows that in the absence of Vav3 expression, retinoblastoma protein (RB) phosphorylation and the subsequent E2F activation do not take place. By combining pharmacological and genetic approaches, phosphatidylinositol-3-kinase and phospholipase Cγ2 (PLCγ2) were identified as the key regulatory signalling molecules upstream of the Vav3/Rac pathway leading to RB phosphorylation and E2F transcription factor activation. Additionally, vav3(-/-) and plcγ2(-/-) DT40 B cells were not able to activate the RB-E2F complex wild-type phenotype when these genetically modified cells were transfected with constitutively active forms of RhoA or Cdc42. However, when these knockout cells were transfected with different constitutively active versions of PLCγ, Vav or Rac1, not only activation of the RB-E2F complex wild-type phenotype was recovered but also the cellular proliferation. Furthermore, by evaluating the effect of two known effector mutants of Rac1 (Rac1(Q61L/F37A) and Rac1(Q61L/Y40C)), the RB-E2F complex activation dependency on p21-activated kinase (PAK) and protein kinase Cε (PKCε) activities was established, being independent of both actin cytoskeleton reorganization and Ras activity. These results suggest that PAK1 and PKCε may be potential therapeutic targets to stop uncontrolled B cell proliferation mediated by the Vav/Rac pathway.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Wiley
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Retinoblastoma Protein
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E2f
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Rac1
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P21 Activated Kinase
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Otras Ciencias Biológicas
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Rac1/p21-activated kinase pathway controls retinoblastoma protein phosphorylation and E2F transcription factor activation in B lymphocytes
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-09-01T18:06:43Z
dc.journal.volume
283
dc.journal.number
4
dc.journal.pagination
647-661
dc.journal.pais
Reino Unido
dc.journal.ciudad
Londres
dc.description.fil
Fil: Zaldua, Natalia. Bizkaia Science and Technology Park; España
dc.description.fil
Fil: LLavero, Francisco. Universidad del País Vasco; España. Bizkaia Science and Technology Park; España
dc.description.fil
Fil: Artaso, Alain. Universidad del País Vasco; España
dc.description.fil
Fil: Gálvez, Patricia. Technological Park of Health Sciences; España
dc.description.fil
Fil: Lacerda, Hadriano M.. Bizkaia Science and Technology Park; España
dc.description.fil
Fil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina
dc.description.fil
Fil: Zugaza, José L.. Universidad del País Vasco; España. Bizkaia Science and Technology Park; España
dc.journal.title
Febs Journal
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/febs.13617/abstract
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info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1111/febs.13617