Smad and AML Proteins Synergistically Confer Transforming Growth Factor beta 1 Responsiveness to Human Germ-line IgA Genes

• Published in: The Journal of biological chemistry 2000-02, Vol.275 (5), p.3552-3560
• Main Authors: Pardali, E, Xie, X, Tsapogas, P, Itoh, S, Arvanitidis, K, Heldin, C, ten Dijke, P, Grundstroem, T, Sideras, P
• Format: Article
• Language: English
• Subjects: activin; ALK4 protein; ALK5 protein; AML protein; class switching; Smad proteins; transforming growth factor-^b
• ISSN: 0021-9258
• DOI: 10.1074/jbc.275.5.3552

Transcription of germ-line immunoglobulin heavy chain genes conditions them to participate in isotype switch recombination. Transforming growth factor- beta 1 (TGF- beta 1) stimulates promoter elements located upstream of the IgA1 and IgA2 switch regions, designated I alpha 1 and I alpha 2, and contributes to the development of IgA responses. We demonstrate that intracellular Smad proteins mediate activation of the I alpha 1 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 I alpha 1 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 I alpha 1 promoter. The I alpha 1 element provides a canape of interspersed high and low affinity sites for Smad and AML factors, some of which are indispensable for TGF- beta responsiveness. While AML super(.)Smad complexes are formed in the cytoplasm of DG75 and K562 cells constitutively, only after TGF- beta receptor activation, novel Smad3 super(.)Smad4 super(.)AML complexes are detected in nuclear extracts by EMSA with I alpha 1 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.