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Genes & Dev. 14 (4): 435-451

Copyright © 2000 by Cold Spring Harbor Laboratory Press.

Vol. 14, No. 4, pp. 435-451, February 15, 2000

RESEARCH PAPER
Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif

Stéphane Germain,1,4 Michael Howell,1,2 Graeme M. Esslemont,2 and Caroline S. Hill1,2,3

1 Laboratory of Developmental Signalling, Imperial Cancer Research Fund, WC2A 3PX London, UK; 2 Ludwig Institute for Cancer Research, W1P 6BT London, UK

We have investigated the regulation of the activin-inducible distal element (DE) of the Xenopus goosecoid promoter. The results show that paired-like homeodomain transcription factors of the Mix family, Mixer and Milk, but not Mix.1, mediate activin/TGF-beta -induced transcription through the DE by interacting with the effector domain of Smad2, thereby recruiting active Smad2/Smad4 complexes to the Mixer/Milk-binding site. We identify a short motif in the carboxyl termini of Mixer and Milk, which is demonstrated to be both necessary and sufficient for interaction with the effector domain of Smad2 and is required for mediating activin/TGF-beta -induced transcription. This motif is not confined to these homeodomain proteins, but is also present in the Smad2-interacting winged-helix proteins Xenopus Fast-1, human Fast-1, and mouse Fast-2. We demonstrate directly that transcription factors of different DNA-binding specificity recruit activated Smads to distinct promoter elements via a common mechanism. These observations, together with the temporal and spatial expression patterns of Mixer and Milk, lead us to propose a model for mesoendoderm formation in Xenopus in which these homeodomain transcription factor/Smad complexes play a role in initiating and maintaining transcription of target genes in response to endogenous activin-like signals.

[Key Words: Activin; homeodomain; Smad; TGF-beta ; transcriptional regulation; Xenopus]


4 Present address: INSERM Unité 36, Collège de France, 3 rue d'Ulm, 75005 Paris, France.

3 Corresponding author.


GENES & DEVELOPMENT 14:435-451 © 2000 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/00 $5.00

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