Identification of a candidate tumor-suppressor gene specifically activated during Ras-induced senescence.
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.
Barradas
Marta
M
Department of Immunology and Oncology, Spanish National Center of Biotechnology (CSIC), Campus de Cantoblanco, Madrid E-28049, Spain.
Gonos
Efstathios S
ES
Zebedee
Zoë
Z
Kolettas
Evangelos
E
Petropoulou
Charikleia
C
Delgado
M Dolores
MD
León
Javier
J
Hara
Eiji
E
Serrano
Manuel
M
D017500:Adenovirus E1A Proteins / Q000378:metabolism / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division; D002460:Cell Line; D016922:Cellular Senescence; D002648:Child; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008565:Membrane Proteins; D008875:Middle Aged; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism* / Q000494:pharmacology
D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; C107465:ERF protein, human; C494069:ETS2 protein, human; D008565:Membrane Proteins; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C449281:TMEM158 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D006861:Hydrogen Peroxide; D018631:ras Proteins