%0 Journal Article
%T Impact of oncogenic K-RAS on YB-1 phosphorylation induced by ionizing radiation
%A Mahmoud Toulany
%A Tim-Andre Schickflu£¿
%A Wolfgang Eicheler
%A Rainer Kehlbach
%A Birgit Schittek
%A H Peter Rodemann
%J Breast Cancer Research
%D 2011
%I BioMed Central
%R 10.1186/bcr2845
%X IR-induced YB-1 phosphorylation in K-RAS wild-type (K-RASwt) and K-RAS-mutated (K-RASmt) breast cancer cell lines was investigated. Using pharmacological inhibitors, small interfering RNA (siRNA) and plasmid-based overexpression approaches, we analyzed pathways involved in YB-1 phosphorylation by IR. Using ¦Ã-H2AX foci and standard colony formation assays, we investigated the function of YB-1 in repair of IR-induced DNA double-stranded breaks (DNA-DSB) and postirradiation survival was investigated.The average level of phosphorylation of YB-1 in the breast cancer cell lines SKBr3, MCF-7, HBL100 and MDA-MB-231 was significantly higher than that in normal cells. Exposure to IR and stimulation with erbB1 ligands resulted in phosphorylation of YB-1 in K-RASwt SKBr3, MCF-7 and HBL100 cells, which was shown to be K-Ras-independent. In contrast, lack of YB-1 phosphorylation after stimulation with either IR or erbB1 ligands was observed in K-RASmt MDA-MB-231 cells. Similarly to MDA-MB-231 cells, YB-1 became constitutively phosphorylated in K-RASwt cells following the overexpression of mutated K-RAS, and its phosphorylation was not further enhanced by IR. Phosphorylation of YB-1 as a result of irradiation or K-RAS mutation was dependent on erbB1 and its downstream pathways, PI3K and MAPK/ERK. In K-RASmt cells K-RAS siRNA as well as YB-1 siRNA blocked repair of DNA-DSB. Likewise, YB-1 siRNA increased radiation sensitivity.IR induces YB-1 phosphorylation. YB-1 phosphorylation induced by oncogenic K-Ras or IR enhances repair of DNA-DSB and postirradiation survival via erbB1 downstream PI3K/Akt and MAPK/ERK signaling pathways.The Y-box binding protein-1 (YB-1), which is a member of a family of DNA-binding proteins, is an oncogenic transcription factor that is highly expressed in breast cancers [1,2], colorectal cancer and cancers of the lung, prostate, ovary and bone. Recently, it was shown that YB-1 induces the expression of CD44 and CD49f, leading to enhanced self-renewal and ma
%U http://breast-cancer-research.com/content/13/2/R28