CBFα3 (AML2) Is Induced by TGF-β1 to Bind and Activate the Mouse Germline Ig α Promoter

Abstract

AbstractTGF-β1 directs class switching to IgA by splenic B cells and by the surface IgM+ B cell line, I.29μ, by inducing germline (GL) Ig α transcripts. The promoter segment between −130 and +46, relative to the first initiation site for mouse GL α transcripts, is sufficient for expression and TGF-β1 inducibility of a reporter gene in B cell lines. Within this segment resides a TGF-β1-responsive element (TβRE) that is required for induction of the promoter by TGF-β1 and, when multimerized, is sufficient to transfer TGF-β1 inducibility to another promoter. In this report we show that a TGF-β1-inducible complex binds the TβRE and contains the transcription factor core-binding factor (CBF; also known as acute myeloid leukemia, AML). Although all three CBFα family members activate the GL α promoter, only CBFα3 (AML-2) is induced by TGF-β1 in splenic B and I.29μ cells. The TβRE contains two CBF binding sites. Mutation of both sites reduces but does not eliminate induction of the GL α promoter by TGF-β1 or by overexpression of CBF, possibly due to the presence of an additional CBF site in the promoter. In addition, the TβRE contains two copies of another sequence motif. Mutation of these motifs eliminates TGF-β1 induction of the GL α promoter. Together the data indicate that TGF-β1 induction of the α promoter involves induction of CBFα3, which binds to the TβRE of the promoter along with one or more proteins.