Abstract

Transforming growth factor (TGF)- induces various cellular responses principally through Smad-dependent transcriptional regulation. Activated Smad complexes cooperate with transcription factors in regulating a group of target genes. The target genes controlled by the same Smad-cofactor complexes are denoted a synexpression group. We found that an Id-like helix-loop-helix protein, human homologue of Maid (HHM), is a synexpression group-restricted regulator of TGF- signalling. HHM suppressed TGF--induced growth inhibition and cell migration but not epithelial–mesenchymal transition. In addition, HHM inhibited TGF--induced expression of plasminogen activator inhibitor-type 1 (PAI-1), PDGF-B, and p21^WAF, but not Snail. We identified a basic-helix-loop-helix protein, Olig1, as one of the Smad-binding transcription factors affected by HHM. Olig1 interacted with Smad2/3 in response to TGF- stimulation, and was involved in transcriptional activation of PAI-1 and PDGF-B. HHM, but not Id proteins, inhibited TGF- signalling-dependent association of Olig1 with Smad2/3 through physical interaction with Olig1. HHM thus appears to regulate a subset of TGF- target genes including the Olig1-Smad synexpression group. HHM is the first example of a cellular response-selective regulator of TGF- signalling with clearly determined mechanisms.

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