Smad and AML proteins synergistically confer transforming growth factor beta1 responsiveness to human germ-line IgA genes.
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.
Pardali
E
E
Division of Tumor Biology, Department of Cell and Molecular Biology, Umeâ University, S-901 87 Umeâ, Sweden.
Xie
X Q
XQ
Tsapogas
P
P
Itoh
S
S
Arvanitidis
K
K
Heldin
C H
CH
ten Dijke
P
P
Grundström
T
T
Sideras
P
P
D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics*; D017578:Immunoglobulin Class Switching; D008969:Molecular Sequence Data; D051898:Smad1 Protein; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta