RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence.
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 KRAS(V12) or BRAF(E600) 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.
Department of Pathology, Vall d'Hebron University Hospital, and Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
Laura
L
López-Vicente
Berta
B
Pons
Laura
L
Coch
Cristina
C
Teixidó
Javier
J
Hernández-Losa
Gemma
G
Armengol
Santiago
S
Ramon Y Cajal
D002478:Cells, Cultured; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D009857:Oncogenes; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000502:physiology; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C501305:RPS6KA6 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048051:p38 Mitogen-Activated Protein Kinases