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Bcr‐Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic‐driven mechanism of protein up‐regulation
Author(s) -
Moorthi Sitapriya,
Burns Tara Ann,
Yu GuiQin,
Luberto Chiara
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701016r
Subject(s) - breakpoint cluster region , biology , messenger rna , abl , microbiology and biotechnology , gene , genetics , signal transduction , tyrosine kinase
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. FASEB J . 32, 4270–4283 (2018). www.fasebj.org