Abstract 1071: Repression of ERK1/2 signaling by RanBPM

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Abstract Ran binding protein-M (RanBPM, also called RanBP9) is a nucleo-cytoplasmic protein that has been implicated in a multitude of cellular roles, including the regulation of transcription, protein modifications and stability, and extracellular receptor signaling pathways. However the precise mechanism by which RanBPM functions within the cell remains largely unknown. Previous studies in our lab have identified RanBPM as a pro-apoptotic protein that mediates its effects through modulation of Bcl-2 levels. Here we present evidence that the effect of RanBPM on apoptosis is mediated, at least in part, through regulation of the ERK1/2 signaling pathway. First, we determined that in addition to Bcl-2, RanBPM also regulated the expression of a second anti-apoptotic factor, Bcl-XL. siRNA-mediated knockdown of RanBPM expression led to elevated Bcl-2 and Bcl-XL mRNA expression, suggesting regulation by RanBPM at the transcriptional level. Conversely, we found that expression of RanBPM also affected ectopically expressed Bcl-2 protein levels. Together, these findings suggested that RanBPM regulated the expression of Bcl-2 and Bcl-XL at both the transcriptional and post-translational levels. One pathway that has previously been shown to regulate the expression of Bcl-2 and Bcl-XL at both the transcriptional and post-translational levels is the ERK1/2 signaling pathway. We found that RanBPM-deficient cells exhibited enhanced ERK1/2 phosphorylation and activation, while re-expression of RanBPM led to a marked decrease in the levels of phosphorylated ERK1/2. Further analyses indicated that enhanced ERK1/2 activation in RanBPM-deficient cells contributed to the elevated levels of Bcl-2 expression observed in these cells, as inhibition of ERK1/2 activation correlated with decreased Bcl-2 protein expression. These findings suggested that RanBPM acts as a novel negative regulator of ERK1/2 signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1071. doi:10.1158/1538-7445.AM2011-1071