Document Detail

Regulation of replicative and stress-induced senescence by RSK4, which is down-regulated in human tumors.
MedLine Citation:
PMID:  19584160     Owner:  NLM     Status:  MEDLINE    
PURPOSE: The control of senescence and its biochemical pathways is a crucial factor for understanding cell transformation. In a large RNA interference screen, the RSK4 gene was found to be related to p53-dependent arrest. The purpose of the present study was to investigate the potential role of RSK4 as a tumor suppressor gene.
EXPERIMENTAL DESIGN: RSK4 expression was determined by quantitative real-time PCR and immunoblot in 30 colon and 20 renal carcinomas, and in 7 colon adenomas. Two HCT116 colon carcinoma cell lines (p53 wt and p53 null), IMR90 human fibroblasts, and E1A-expressing IMR90 cells were infected with RSK4 cDNA and/or shRNA. RSK4 expression levels were analyzed in HCT116 p53 wt or p53 null and IMR90 after senescence induction by quantitative real-time PCR and Western blot.
RESULTS: The RSK4 gene was down-regulated in 27 of 30 colon carcinomas (P < 0.001), 16 of 20 renal cell carcinomas (P < 0.01), and 6 of 7 colon adenomas (P < 0.01). In vitro overexpression of RSK4 induced cell arrest and senescence features in normal fibroblasts and malignant colon carcinoma cell lines. Interestingly, in these cell lines RSK4 mRNA levels were increased both in replicative and stress-induced senescence. Moreover, IMR90 partially immortalized by RSK4 shRNA and HCT116 with this short hairpin RNA were more resistant to cisplatin treatment. Finally, cells expressing E1A or Rb short interfering RNA were resistant to RSK4-mediated senescence.
CONCLUSION: These results support the concept that RSK4 may be an important tumor suppressor gene by modulating senescence induction and contributing to cell proliferation control in colon carcinogenesis and renal cell carcinomas.
Laura López-Vicente; Gemma Armengol; Berta Pons; Laura Coch; Elisabet Argelaguet; Matilde Lleonart; Javier Hernández-Losa; Inés de Torres; Santiago Ramon y Cajal
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-07-07
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  15     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-16     Completed Date:  2009-09-28     Revised Date:  2012-06-26    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4546-53     Citation Subset:  IM    
Department of Pathology, Vall d'Hebron University Hospital, and Department of Biochemistry and Molecular Biology, and Unit of Biological Anthropology, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
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MeSH Terms
Antineoplastic Agents / pharmacology
Blotting, Western
Cell Aging / genetics,  physiology*
Cell Line
Cell Proliferation / drug effects
Cisplatin / pharmacology
Colonic Neoplasms / genetics,  metabolism,  pathology
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
DNA Replication*
Down-Regulation / drug effects
HCT116 Cells
Hydrogen Peroxide / pharmacology
Kidney Neoplasms / genetics,  metabolism,  pathology
Neoplasms / genetics,  metabolism,  pathology*
Oxidants / pharmacology
Oxidative Stress / physiology*
RNA, Small Interfering / genetics
Retinoblastoma Protein / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Ribosomal Protein S6 Kinases, 90-kDa / genetics*,  metabolism
Tumor Suppressor Protein p53 / metabolism
Reg. No./Substance:
0/Antineoplastic Agents; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Oxidants; 0/RNA, Small Interfering; 0/Retinoblastoma Protein; 0/Tumor Suppressor Protein p53; 15663-27-1/Cisplatin; 7722-84-1/Hydrogen Peroxide; EC protein, human; EC Protein S6 Kinases, 90-kDa

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