An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-β signalling

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Abstract
Transforming growth factor (TGF)‐β 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‐β signalling. HHM suppressed TGF‐β‐induced growth inhibition and cell migration but not epithelial—mesenchymal transition. In addition, HHM inhibited TGF‐β‐induced expression of plasminogen activator inhibitor‐type 1 (PAI‐1), PDGF‐B, and p21WAF, 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‐β stimulation, and was involved in transcriptional activation of PAI‐1 and PDGF‐B. HHM, but not Id proteins, inhibited TGF‐β signalling‐dependent association of Olig1 with Smad2/3 through physical interaction with Olig1. HHM thus appears to regulate a subset of TGF‐β target genes including the Olig1‐Smad synexpression group. HHM is the first example of a cellular response‐selective regulator of TGF‐β signalling with clearly determined mechanisms.