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 Id2 gene is one of several "Id-like" genes which encode helix-loop-helix proteins which dimerize with basic helix-loop-helix proteins and inhibit binding to the DNA enhancer element known as an E box. By repressing the DNA binding activity of basic helix-loop-helix proteins, Id proteins inhibit transcription of tissue-specific genes in myoblasts, hematopoietic precursor cells, and other types of undifferentiated cells. Serum starvation results in the disappearance of Id gene transcripts in most types of cultured cells, and often induces differentiation of these cells. In order to gain some insight into this process, we have analyzed Id2 promoter function in the glioma cell line U87Y. We have isolated 300 base pairs of Id2 promoter sequence which is sufficient to repress the activity of a reporter gene in serum-starved U87Y cells, but induces the activity of the reporter gene when the cells are stimulated with fresh serum. Two regions within this 300 base pair sequence contain repressor elements; deletion of either region results in increased promoter activity. Both repressor regions serve as binding sites for a protein present in extracts from serum-starved U87Y cells but not in serum-stimulated cells.
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