ID helix-loop-helix proteins

The helix-loop-helix (HLH) family of transcription factors comprises >200 members, which have been identified in organisms from yeast to man (reviewed in Littlewood and Evan, 1995; Massari and Murre, 2000). In metazoa, HLH proteins function in the coordinate regulation of gene expression, orchestrating cell cycle control, cell lineage commitment and cell differentiation. An essential role has been established for a number of HLH proteins in the development of haemopoietic, myogenic, pancreatic and neurogenic mammalian cell lineages. Four main groups of HLH protein can be distinguished on the basis of the presence or absence of additional functional domains (Fig. 1). The highly conserved HLH region comprises two amphipathic α helices, each 15-20 residues long, which are separated by a shorter intervening loop that has a more variable length and sequence. The HLH domain primarily mediates homoor hetero-dimerisation, which is essential for DNA binding and transcriptional regulation. Nearly all HLH proteins possess a region of highly basic residues adjacent to the HLH domain (Fig. 1), which facilitates binding to DNA containing the canonical ‘E box’ recognition sequence, CANNTG. Some HLH proteins also bind the related ‘N box’ sequence, CACNAG (Massari and Murre, 2000). However, a distinct subfamily of HLH proteins, the ID proteins, lack such a DNA-binding region and instead function solely by dimerisation with other transcriptional regulators, principally those of the bHLH type (Fig. 1). Such ID-bHLH heterodimers are unable to bind to DNA, and hence ID proteins act as dominant negative regulators of bHLH proteins (Benezra et al., 1990; Garrell and Mondolell, 1990; Ellis et al., 1990). Since most bHLH proteins positively regulate sets of genes during cell fate determination and cell differentiation, the term ‘ID’ conveniently alludes to the ability of these proteins to inhibit both DNA binding and differentiation. Genes encoding ID proteins have been isolated from several metazoan species, but have been most studied in Drosophila, in which a single Id-like locus, extramacrochaetae (emc), encodes an ID-like protein (Garrell and Mondolell, 1990; Ellis et al., 1990), and in mammals (mouse and man), which possess four Id family members (Id1-Id4) (Benezra et al., 1990; Sun et al., 1991; Christy et al., 1991; Biggs et al., 1992; Riechmann et al., 1994). These proteins range in size from 119 residues (ID3) to 199 residues (EMC). Outside the highly conserved HLH domain, the different ID proteins display extensive sequence divergence. Although ID proteins traditionally have been viewed as negative regulators of cell differentiation, recent work has revealed much wider biological roles for this family of regulatory proteins, which impinge on the fields of developmental biology, cell cycle research and tumour biology (see Table 1). Here, I highlight recent developments in our 3897 Journal of Cell Science 113, 3897-3905 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 JCS1100C