Bcr-Abl (break-point cluster region-abelson)， the oncogenic trigger of chronic myelogenous leukemia (CML)， has previously been shown to up-regulate the expression and activity of sphingomyelin synthase 1 (SMS1)， which contributes to the proliferation of CML cells; however， the mechanism by which this increased expression of SMS1 is mediated remains unknown. In the current study， we show that Bcr-Abl enhances the expression of SMS1 via a 30-fold up-regulation of its transcription. Of most interest， the Bcr-Abl-regulated transcription of SMS1 is initiated from a novel transcription start site (TSS) that is just upstream of the open reading frame. This shift in TSS utilization generates an SMS1 mRNA wi... More
Bcr-Abl (break-point cluster region-abelson)， the oncogenic trigger of chronic myelogenous leukemia (CML)， has previously been shown to up-regulate the expression and activity of sphingomyelin synthase 1 (SMS1)， which contributes to the proliferation of CML cells; however， the mechanism by which this increased expression of SMS1 is mediated remains unknown. In the current study， we show that Bcr-Abl enhances the expression of SMS1 via a 30-fold up-regulation of its transcription. Of most interest， the Bcr-Abl-regulated transcription of SMS1 is initiated from a novel transcription start site (TSS) that is just upstream of the open reading frame. This shift in TSS utilization generates an SMS1 mRNA with a substantially shorter 5' UTR compared with its canonical mRNA. This shorter 5' UTR imparts a 20-fold greater translational efficiency to SMS1 mRNA， which further contributes to the increase of its expression in CML cells. Therefore， our study demonstrates that Bcr-Abl increases SMS1 protein levels via 2 concerted mechanisms: up-regulation of transcription and enhanced translation as a result of the shift in TSS utilization. Remarkably， this is the first time that an oncogene-Bcr-Abl-has been demonstrated to drive such a mechanism that up-regulates the expression of a functionally important target gene， SMS1.-Moorthi， S.， Burns， T. A.， Yu， G.-Q.， Luberto， C. Bcr-Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic-driven mechanism of protein up-regulation.
