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J Biol Chem, Vol. 275, Issue 5, 3552-3560, February 4, 2000
1 Responsiveness to Human Germ-line IgA Genes*
§¶,§,,
,,,,, and**
From the Transcription of germ-line immunoglobulin heavy
chain genes conditions them to participate in isotype switch
recombination. Transforming growth factor- Division of Tumor Biology, Department of
Cell and Molecular Biology, Umeå University, S-901 87 Umeå, the
Ludwig Institute for Cancer Research, Box 595, Biomedical
Center, S-751 24 Uppsala, and the ** Department of Inflammation
Pharmacology, ASTRAZENECA R&D LUND, S-22100 Lund, Sweden
1 (TGF-1) stimulates
promoter elements located upstream of the IgA1 and IgA2 switch regions,
designated I
1 and I2, and contributes to the development of IgA
responses. We demonstrate that intracellular Smad proteins mediate
activation of the I1 promoter by TGF-. TGF- type 1 receptor
(ALK-5), activin type IB receptor (ALK-4), and the "orphan" ALK-7
trans-activate the I1 promoter, thus raising the possibility that
other members of the TGF- superfamily can also modulate IgA
synthesis. Smads physically interact with the AML family of
transcription factors and cooperate with them to activate the I1
promoter. The I1 element provides a canapé of interspersed
high and low affinity sites for Smad and AML factors, some of which are
indispensable for TGF- responsiveness. While AML·Smad complexes
are formed in the cytoplasm of DG75 and K562 cells constitutively, only
after TGF- receptor activation, novel Smad3·Smad4·AML complexes
are detected in nuclear extracts by EMSA with I1 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.
To whom correspondence should be addressed. Tel.:
46-90-7852528; Fax: 46-90-771420; E-mail:
Paschalis.Sideras@cmb.umu.se.
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