RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence
López-Vicente, Laura (Hospital Universitari Vall d'Hebron. Servei de Patologia)
Pons López, Berta (Hospital Universitari Vall d'Hebron. Servei de Patologia)
Coch, Laura (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Teixidó, Cristina (Hospital Universitari Vall d'Hebron. Servei de Patologia)
Hernandez-Losa, Javier (Hospital Universitari Vall d'Hebron. Servei de Patologia)
Armengol Rosell, Gemma (Universitat Autònoma de Barcelona. Departament de Biologia Animal, de Biologia Vegetal i d'Ecologia)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron. Servei de Patologia)

Data:	2011
Resum:	p90 Ribosomal S6 kinase (RSK) 4 is a serine-threonine kinase that belongs to the p90RSK family. RSK4 has been proposed as a tumor suppressor gene, related with anti-invasive activity, inhibition of the RAS-mitogen-activated protein kinase (MAPK) pathway and induction of senescence. Despite the related findings, little is known about RSK4 effectors. In human tumors, RSK4 is downregulated even in some benign lesions, such as colon adenomas and breast papillomas, indicating that RSK4 inhibition could be an early event in cellular transformation. For cells to achieve immortality and transformation, it is believed that they must override senescence. In the present study, we found that when RSK4 is inhibited in vitro using short hairpin RNA technology, cells can bypass stress-induced senescence and oncogene-induced senescence: normal human fibroblasts grew following oxidative stress, induction of DNA damage and KRASV12 or BRAFE600 overexpression. To investigate the RSK4 effectors, we used short hairpin RNA or inhibitor molecules against major senescence mediators. We found that RSK4-induced senescence is mediated through p21, but is independent of p16, p38MAPKs and induction of reactive oxygen species, delimiting RSK4 signaling. These data support the importance of RSK4 for regulating senescence and indicate that downregulation of this kinase could be an important element in facilitating cell transformation.
Ajuts:	Fundació la Marató de TV3 052710 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-0756 Agència de Gestió d'Ajuts Universitaris i de Recerca 2005/SGR-00144
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Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Matèria:	Cancer Biology
Publicat a:	Carcinogenesis, Vol. 32, issue 4 (April 2011) , p. 470-476, ISSN 1460-2180

DOI: 10.1093/carcin/bgr003

Postprint 35 p, 1.3 MB

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