Identification and Functional Characterization of Distinct Critically Important Bone Morphogenetic Protein-specific Response Elements in the Id1 Promoter (original) (raw)

2002, Journal of Biological Chemistry

Transforming growth factor-␤ (TGF-␤) family members, which include bone morphogenetic proteins (BMPs) and TGF-␤s, elicit their cellular effects by activating specific Smad proteins, which control the transcription of target genes. BMPs and TGF-␤s have overlapping as well as specific effects on mesenchymal cell differentiation for which the mechanisms are incompletely understood. Here we report that Id1, a dominant negative inhibitor of basic helix-loop-helix proteins, is a direct target gene for BMP. BMP, but not TGF-␤, strongly activates the Id1 promoter in an Smad-dependent manner. We identified two BMP-responsive regions in the mouse Id1 promoter, which contain three distinct sequence elements; one region contains two Smad binding elements (SBEs), and the other region contains a GGCGCC palindromic sequence flanked by two CAGC and two CGCC motifs. Whereas SBEs and GGCGCC sequence are critically important, the CAGC and CGCC motifs are needed for efficient BMP-induced Id1 promoter activation. Smads are part of nuclear transcription factor complexes that specifically bind to SBEs and GGCGCC sequence in response to BMP but not TGF-␤. Multimerization of the all three distinct sequence motifs is needed to generate a highly sensitive and BMP/Smaddependent specific enhancer. Our results provide important new insights into how the BMP/Smad pathway can specifically activate target genes. Depending on their extracellular stimuli, mesenchymal precursor cells can differentiate into muscle, fat, bone, or cartilage. Members of the transforming growth factor-␤ superfamily, which includes TGF-␤s, 1 activins, and bone morphogenetic proteins (BMPs), have important roles in directing cell fate choices of mesenchymal cells (1-3). BMPs stimulate osteoblast differentiation and inhibit myogenic differentiation (4-6). TGF-␤s and activins inhibit myogenic and late osteoblast differentiation (2, 7-9). The mechanisms that govern the ability of different TGF-␤ family members to induce similar but also specific differentiation effects are unclear.