Abstract
Transcription of germ-line immunoglobulin heavy chain genes conditions them to participate in isotype switch recombination. Transforming growth factor-beta1 (TGF-beta1) stimulates promoter elements located upstream of the IgA1 and IgA2 switch regions, designated Ialpha1 and Ialpha2, and contributes to the development of IgA responses. We demonstrate that intracellular Smad proteins mediate activation of the Ialpha1 promoter by TGF-beta. TGF-beta type 1 receptor (ALK-5), activin type IB receptor (ALK-4), and the "orphan" ALK-7 trans-activate the Ialpha1 promoter, thus raising the possibility that other members of the TGF-beta superfamily can also modulate IgA synthesis. Smads physically interact with the AML family of transcription factors and cooperate with them to activate the Ialpha1 promoter. The Ialpha1 element provides a canapé of interspersed high and low affinity sites for Smad and AML factors, some of which are indispensable for TGF-beta responsiveness. While AML.Smad complexes are formed in the cytoplasm of DG75 and K562 cells constitutively, only after TGF-beta receptor activation, novel Smad3.Smad4.AML complexes are detected in nuclear extracts by EMSA with Ialpha1 promoter-derived probes. Considering the wide range of biological phenomena that AMLs and Smads regulate, the physical/functional interplay between them has implications that extend beyond the regulation of class switching to IgA.
Highlights
Production of the appropriate antibody isotypes during a humoral immune response is an important prerequisite for the development of protective humoral immunity
We have recently shown that the DRE element contains functional binding sites for transcription factors of the acute myeloid leukemia (AML) family [14], and that AML proteins cooperate with transcription factors of the Ets family to activate the I␣1 promoter
Three ␣ chains are encoded by the AML1 (CBFA2/PEBP2␣B), AML2 (CBFA3/PEBP2␣C), and AML3 (CBFA1/PEBP2␣A) genes and one  subunit is encoded by the PEBP2 (CBF) gene
Summary
Production of the appropriate antibody isotypes during a humoral immune response is an important prerequisite for the development of protective humoral immunity. We demonstrate that the I␣1 promoter contains an array of interspersed functional Smad and AML-binding sites that mediate in a cooperative manner the TGF- responsiveness of this element.
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