The expression patten of Id4, a novel dominant negative helix-loop-helix protein, is distinct from Id1, Id2 and Id3

Max-Delbrück-Laboratorium in der Max-Planck-Gesellschaft Carl-von-Linné-Weg 10, Köln, Germany.
Nucleic Acids Research (Impact Factor: 9.11). 04/1994; 22(5):749-55.
Source: PubMed

ABSTRACT Molecular interaction between transcription factors containing an basic-helix-loop-helix (bHLH) domain is known to regulate differentiation in several cellular systems including myogenesis, neurogenesis and haematopoiesis. DNA-binding activity of the bHLH proteins is mediated via the basic region and is dependent upon formation of homo- and/or heterodimers of these transcription factors. Dominant negative (dn) HLH proteins (Id1, Id2, Id3 and emc) also contain the HLH-dimerization domain but lack the DNA-binding basic region. Formation of heterodimers between dnHLH and bHLH proteins abolishes the DNA-binding activity of the latter. Concordantly, it was shown that the dnHLH protein Id1 inhibits differentiation of muscle and myeloid cells in vitro. Therefore, it was postulated that dnHLH proteins serve as general antagonists of cell differentiation. We have isolated and characterized a novel mouse dnHLH gene, designated Id4. The Id4 protein contains a HLH domain highly conserved among the dnHLH proteins from mouse and drosophila. Outside of the HLH domain, three additional short regions of the dnHLH proteins show some degree of homology. DNA-binding of E47 homo- as well as E47/MyoD heterodimers is inhibited by Id4. Transcription of the Id4 gene results in three RNA molecules of 3.7, 2.0 and 1.7 kb which are presumably a result of differential splicing and/or alternatively used polyadenylation sites within the 3' untranslated region. During embryogenesis, Id4 expression is up-regulated between day 9.5 and 13.5 of gestation. The highest expression in adult tissues was detected in testis, brain and kidney. Comparison of the expression patterns of the four mouse dnHLH genes revealed that Id4 expression differs from the more restricted expression of Id2 as well as from the widespread expression of Id1 and Id3.

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Available from: Fred Sablitzky, Sep 26, 2015
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    • "The majority of chirality defects and all of the rotation defects that are seen in emc mutants (Fig. 7) (Brown et al., 1995; Bhattacharya and Baker, 2009) are likely to be due to dysregulation of Wg signaling and other factors. Four emc homologs encoded within the vertebrate genome are referred to as the inhibitor of DNA binding genes (Id1-4) (Benezra et al., 1990; Christy et al., 1991; Sun et al., 1991; Biggs et al., 1992; Ellmeier et al., 1992; Deed et al., 1993; Riechmann et al., 1994; Zhu et al., 1995). To date, a role for the Id proteins in D/V patterning of the vertebrate retina has not been reported. "
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    ABSTRACT: One of the seminal events in the history of a tissue is the establishment of the anterior-posterior, dorsal-ventral (D/V) and proximal-distal axes. Axis formation is important for the regional specification of a tissue and allows cells along the different axes to obtain directional and positional information. Within the Drosophila retina, D/V axis formation is essential to ensure that each unit eye first adopts the proper chiral form and then rotates precisely 90° in the correct direction. These two steps are important because the photoreceptor array must be correctly aligned with the neurons of the optic lobe. Defects in chirality and/or ommatidial rotation will lead to disorganization of the photoreceptor array, misalignment of retinal and optic lobe neurons, and loss of visual acuity. Loss of the helix-loop-helix protein Extramacrochaetae (Emc) leads to defects in both ommatidial chirality and rotation. Here, we describe a new role for emc in eye development in patterning the D/V axis. We show that the juxtaposition of dorsal and ventral fated tissue in the eye leads to an enrichment of emc expression at the D/V midline. emc expression at the midline can be eliminated when D/V patterning is disrupted and can be induced in situations in which ectopic boundaries are artificially generated. We also show that emc functions downstream of Notch signaling to maintain the expression of four-jointed along the midline. © 2015. Published by The Company of Biologists Ltd.
    Development 03/2015; 142(5):1006-15. DOI:10.1242/dev.120618 · 6.46 Impact Factor
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    • "A member of the ID protein family, ID4, regulates cell proliferation and differentiation [17,18]. ID4 was originally identified as a novel dominant-negative basic helix-loop-helix (bHLH) transcription factor distinct from ID1, ID2, and ID3 [19-22]. Heterodimerisation of ID4 with other bHLH proteins facilitates dominant-negative regulation [23]. "
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    ABSTRACT: Background The periodontal ligament (PDL), connective tissue located between the cementum of teeth and alveolar bone of the mandibula, plays an important role in the maintenance and regeneration of periodontal tissues. We reported previously that endoglin was involved in the BMP-2-induced osteogenic differentiation of mouse PDL cells, which is associated with Smad-2 phosphorylation but not Smad-1/5/8 phosphorylation. In this study, to elucidate the detailed mechanism underlying the BMP-2 signalling pathway unique to PDL cells, we performed a microarray analysis to identify BMP-2-inducible genes in PDL-L2 cells, a mouse PDL-derived cell line, with or without endoglin knockdown. Findings Sixty-four genes were upregulated more than twofold by BMP-2 in PDL-L2 cells. Of these genes, 11 were endoglin-dependent, including Id4, which encodes ID4, a helix-loop-helix transcription factor closely associated with TGF-β signaling and osteoblast differentiation. The endoglin-dependent induction of ID4 by BMP-2 was also verified at a protein level. Conclusion Our findings indicate that ID4 could be a signal mediator involved in the BMP-2-induced endoglin-dependent osteogenic differentiation of PDL cells.
    Journal of Molecular Signaling 11/2014; 9(1):5. DOI:10.1186/1750-2187-9-5
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    • "To date, four members of the Id gene family have been described (Id1-Id4) [12,13]. They are located on different chromosomes and have different expression patterns and functions. "
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    ABSTRACT: Background Salivary gland cancer (SGC) is one of the common malignancies of the head and neck area. It develops in the minor and major salivary glands and sometimes metastasizes to other organs, particularly to the lungs. Inhibitors of differentiation (Id) proteins are negative regulators of basic helix-loop-helix transcription factors that control malignant cell behavior and tumor aggressiveness in many tissues. In this study, our goal was to determine the potential role of Id proteins, particularly Id1, during human SGC cell progression. Methods We first determined the expression levels of Id1 and Id2 in four SGC cell lines: two adenocarcinoma of the salivary gland (HSG and HSY) and two adenoid cystic carcinoma (ACC2 and ACCM) cell lines. We then used constructs that expressed antisense cDNAs to Id1 or Id2 to knockdown the expression of these proteins in cell lines where they were highly expressed, and determined the effects of the knockdown on cell proliferation, migration and invasion. Results Id1 mRNA and protein were detectable in all cell lines, and expression of Id2 was variable, from absent to high. The ACC2 and ACCM cell lines expressed both Id1 and Id2, but Id1 was expressed at a higher level in the more aggressive ACCM cell line in comparison toACC2 cells as confirmed by Id1 promoter-reporter assays. We therefore focused on the ACCM cells for the remainder of the study. We found that proliferation and invasiveness of ACCM cells were strongly reduced after Id1 knockdown whereas Id2 suppression had only a slight effect. Results of scratch and colony formation assays also confirmed that ACCM cell aggressiveness was significantly reduced upon Id1 knockdown. Finally, this knockdown resulted in reduced c-myc and enhanced cyclin-dependent kinase inhibitor p21 expression. Conclusions These results demonstrate that Id1 plays an important role in the control of human SGC cell aggressiveness and suggest a potential role as a marker of diagnosis, prognosis and progression of SGCs. Id1 suppression could represent a novel and effective approach for the treatment of salivary gland cancer.
    BMC Cancer 03/2013; 13(1):141. DOI:10.1186/1471-2407-13-141 · 3.36 Impact Factor
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