The Id proteins were the first identified naturally occurring dominant negative antagonists of a transcription factor class. They have been shown to control a wide range of cell fate decisions in embryonic and adult development in organisms ranging from fly to man (1, 2). The four related members of the family (called Id1–4) all contain a helix-loop-helix (HLH) dimerization motif. The 40- to 50-amino acid HLH domain is found in many transcription factors, including the myc family of cellular oncogenes, MyoD, other E-box (CANNTG)- binding proteins, and hypoxia inducible factor (HIF)-1α. Most of these HLH-containing transcription factors have an extra basic region (hence the term bHLH proteins) that specifically binds to DNA. In contrast, the Id proteins lack the basic region. Consequently, Id proteins bind to and sequester bHLH proteins, preventing their homo- or heterodimerization with other bHLH factors and their association with DNA. Principal targets of the Id proteins are the ubiquitously expressed bHLH E-proteins, which cooperate with tissue-restricted bHLH proteins to regulate gene expression (1, 3, 4). Thus Id– E-protein interactions provide a unifying mechanism for controlling cell-type–specific gene expression in multiple cell lineages.

Loss-of-function mutations in Id1 and Id3 have been shown to lead to embryonic and adult angiogenic defects, suggesting an important role for these proteins in blood vessel formation (5). Based on a consideration of underlying transcriptional mechanisms, it seems likely that such defects are related to the liberation of otherwise Id-sequestered E-proteins and the inappropriate activation of genes under the control of bHLH transcription factors. Although the identification of E-protein partners in endothelial cells (ECs) remains elusive, certain downstream consequences of Id loss are gradually coming to light.