A human Id-like helix-loop-helix protein expressed during early development.

Abstract

The interaction of helix-oop-helix (HLH) proteins is known to regulate the differentiation of several different tissues, including mammalian muscle and the insect peripheral nervous system. In myoblasts, the products of myogenic HLH genes such as MyoD and ubiquitous HLH proteins such as E12 are present at constant levels throughout development. An E12 monomer and a MyoD monomer form a DNA binding heterodimer that activates muscle-specific genes. These two proteins are unable to dimerize in proliferating myoblasts because a negative regulator HLH protein, Id, is present. We now report the sequence and structure of a human HLH gene related to Id, which has been designated Id-2. Two prominent Id-2 RNA molecules of 2.5 and 1.3 kilobases were found in a number of different human normal and neoplastic tissues. We believe the larger RNA is a precursor of the 1.3-kilobase mRNA that encodes an Id-2 protein of 134 amino acids. The HLH region of the Id-2 protein is 90% homologous to that of myogenic Id, but the homology is much less extensive outside the HLH region. The Id-2 gene is highy expressed during early fetal development in several tissues, including those of the central nervous system, but is not expressed in the correspondin mature tissues. Id-2 expression Is modulated in assciation with retinoic acid-induced ganglionic differentiation of the neuroblastoma cell line SMS-KCNR. These findings suggest that Id-2 is an inhibitor of tissue-specific gene expression, although its distinctive pattern of expression during development suggests a role different from that of Id.Transcription factors containing the helix-loop-helix (HLH) motif regulate the expression of tissue-specific genes in a number ofmammalian and insect tissues, including the insect peripheral nervous system (PNS) (1). During development of the PNS in Drosophila, HLH genes such as daughterless and the achete/scute genes are required for neurogenesis (2). The activity of these genes is apparently opposed by another HLH gene, extramacrochaetae (emc), which may function by forming heterodimers with the achete and scute genes (3). Biochemical evidence for the inhibition ofgene expression by such a mechanism is best defined in studies of mammalian myogenesis. During the proliferation and differentiation of myoblasts, the products of myogeneic HLH genes such as MyoD (4) and ubiquitous HLH proteins such as E12 (5) Similarly, the emc gene of Drosophila lacks such a basic DNA binding domain, providing yet additional evidence that the model proposed for regulation of muscle-specific gene expression will be paralleled in other tissues (4). We have sought Id-like proteins that would be candidates for regulating the expression of lineage-specific genes in mammalian tissues other than muscle. Because mammalian homologues of the achete complex are known to be HLH proteins that may function as positive regulators of gene expression in neural crest precursors of the rat PNS, we were particularly interested in examining nervous system tissues for the presence o...

The genes for the helix-loop-helix proteins Id6a, Id6b, Id1 and Id2 are specifically expressed in the ventral and dorsal domains of the fish developing somites

“…The experimental inactivation of the Id2-gene locus does not lead to an apparent alteration of kidney development (Yokota et al, 1999). Nevertheless, our observation emphasizing a high level of Id2 transcription in the pronephros is in agreement with the strong accumulation of Id2 transcript reported in the developing kidney of Xenopus (Wilson and Mohun, 1995) and humans (Biggs et al, 1992) as well as in the adult kidney of trout (Rescan, 1997). Interestingly, an involvement of Id2 in regulating gene transcription in the kidney is suggested by in vitro data showing that Id2 interacts directly with Pax-2 and Pax-8 proteins, both of which are expressed in the kidney (Roberts et al, 2001).…”

The Helix–Loop–Helix Protein Id-1 Delays Onset of Replicative Senescence in Human Endothelial Cells

“…As Id-1 expression promotes cellular proliferation and inhibits differentiation in many cell types, it is a natural focus of studies examining the molecular mechanisms of tumor development. Although not comprehensively studied, reports indicate that Id-1 is overexpressed in cells derived from several types of tumors, including pancreatic cancer, lung cancer, breast cancer, neuroblastoma, neuroepithelioma, astrocyte tumors, and endometrial cancers (Andres-Barquin et al, 1997;Biggs et al, 1992;Lin et al, 2000;Maruyama et al, 1999;Takai et al, 2001;Zhu et al, 1995). Indeed, recent studies have indicated that higher levels of Id-1 expression may be related to more aggressive tumors (Lin et al, 2000;Takai et al, 2001 …”

Expression of the helix‐loop‐helix gene Id3 during murine embryonic development

“…This gene represents one of four members of the mammalian "Idlike" dominant-negative HLH (dnHLH) gene family. The three other genes in this family are designated Id1 (Benezra, 19901, Id2 (Sun et al, 1991;Biggs et al, 1992), and Id4 (Riechmann et al, 1994), respectively. All four genes, although clearly distinct, share common features, such as the presence of a HLH dimerization domain and the lack of a basic DNA-binding domain.…”

“…One is designated Id2 (Sun et al, 1991;Biggs et al, 1992). Another gene has been characterized in the mouse as a gene called HLH462 (Christy et al, 1991) and in human as HEIR1 or HLHlR2l (Deed et al, 1993).…”