Identification of a candidate tumor-suppressor gene specifically activated during Ras-induced senescence (Journal article)

Barradas, M./ Gonos, E. S./ Zebedee, Z./ Kolettas, E./ Petropoulou, C./ Delgado, M. D./ Leon, J./ Hara, E./ Serrano, M.

Normal cells display protective responses against oncogenes. Notably, oncogenic Ras triggers an irreversible proliferation arrest that is reminiscent of replicative senescence and that is considered a relevant tumor-suppressor mechanism. Here, we have used microarrayed filters to identify genes specifically upregulated in Ras-senescent human fibroblasts. Among the initial set of genes selected from the microarrays, we found the cell-cycle inhibitor p21(Cip1/Waf1), thus validating the potency of the screening to identify markers and mediators of Ras-senescence. A group of six genes, formed by those more highly upregulated during Ras-senescence, was analyzed in further detail to evaluate their specificity. In particular, we examined their expression in cells overexpressing Ras but rendered resistant to Ras-senescence by the viral oncoprotein E1a; also, we have studied their expression during replicative senescence, organismal aging, H(2)O(2)-induced senescence, and DNA damage. In this manner, we have identified a novel gene, RIS1 (for Ras-induced senescence 1), which is not upregulated in association to any of the above-mentioned processes, but exclusively during Ras-senescence. Furthermore, RIS1 is also upregulated by the transcriptional factor Ets2, which is a known mediator of Ras-induced senescence. Interestingly, RIS1 is located at chromosomal position 3p21.3 and, more specifically, it is included in a short segment of just 1 Mb previously defined by other investigators for its tumor-suppressor activity. In summary, we report the identification of a novel gene, RIS1, as a highly specific marker of Ras-induced senescence and a candidate tumor-suppressor gene.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Keywords: Adenovirus E1A Proteins/metabolism/pharmacology,Adolescent,Adult,Aged,Aged, 80 and over,Cell Aging,Cell Division,Cell Line,Child,DNA Damage,*DNA-Binding Proteins,Female,Fibroblasts/cytology/drug effects,*Genes, Tumor Suppressor,Humans,Hydrogen Peroxide/pharmacology,Membrane Proteins,Middle Aged,Proto-Oncogene Protein c-ets-2,Proto-Oncogene Proteins/metabolism,*Repressor Proteins,Trans-Activators/metabolism,*Transcription Factors,*Transcriptional Activation,Tumor Suppressor Proteins/*genetics,Up-Regulation,ras Proteins/*metabolism/pharmacology
URI: https://olympias.lib.uoi.gr/jspui/handle/123456789/21061
ISSN: 0014-4827
Link: http://www.ncbi.nlm.nih.gov/pubmed/11822868
http://ac.els-cdn.com/S0014482701954345/1-s2.0-S0014482701954345-main.pdf?_tid=f1e4f1c724942279d52c19f7490a2c3e&acdnat=1332999248_c59a8ac9983c5733200a166f91441769
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