Disease relevance of Id1

• They are also expressed at high levels in the endothelial cells of tumor-infiltrating blood vessels, and breast tumors spontaneously arising in MMTV-neu mice demonstrate impaired angiogenesis when growing in an Id1- and/or Id3-deficient background [1].
• Antisense oligonucleotide blockade of Id protein expression inhibited the proliferation of human adenocarcinoma cells [2].
• Taken together, these data imply that deregulated expression of Id proteins in colorectal adenocarcinoma arises at least in part as a consequence of loss of p53 function and contributes to the uncontrolled proliferation of tumor cells in colorectal cancer [2].
• No elevation of Id expression was observed in 17 cases of adenoma [2].
• p204 protein overcomes the inhibition of the differentiation of P19 murine embryonal carcinoma cells to beating cardiac myocytes by Id proteins [3].

High impact information on Id1

• BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3 [4].
• In the B cell lineage, the Id1 and Id2 genes are expressed in pro-B cells and down-regulated during differentiation [5].
• Constitutive expression of the Id1 gene impairs mouse B cell development [5].
• Id is expressed at varying levels in all cell lines tested [6].
• Transfection experiments indicate that over-expression of Id inhibits the trans-activation of the muscle creatine kinase enhancer by MyoD [6].

Chemical compound and disease context of Id1

• Down-regulation of Id1 mRNA is associated with dimethyl sulfoxide-induced terminal differentiation of mouse erythroleukemia cells [7].
• Our results suggest that Id-1 can control the malignant progression of breast cancer cells, particularly that mediated by sex steroid hormones [8].
• Analyses using insulinoma cells revealed that Id-1 and Id-3 mRNA concentrations peaked 30 min after glucose was added, returned to near basal concentrations by 2 h and then progressively increased for 24 h [9].
• Inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of androgen-independent prostate cancer cell growth [10].
• Distinct tumor stage-specific inhibitory effects of 2-methoxyestradiol in a breast cancer mouse model associated with Id-1 expression [11].

Biological context of Id1

• Id1 and Id3 have extensive sequence homology and similar patterns of expression during embryogenesis and in adult tissues [1].
• Forced expression of Id1, either by transient transfection or under the control of an inducible system, causes degradation of myogenin in the absence of BMP-2 [12].
• Finally, mutagenesis experiments showed that the differences between Id1 and Id3 binding map to three amino acids in the first helix and to a small cluster of upstream residues [13].
• On the basis of these data, it is speculated that CSN-mediated phosphorylation inhibits ubiquitination of Id1 and Id3 [14].
• By binding to basic HLH transcription factors, Id proteins regulate gene expression [1].

Anatomical context of Id1

• Proteasome-dependent degradation of endogenous Id1 in HeLa cells is also stimulated by treatment with curcumin or emodin [14].
• Id1, 2, and 3 are expressed in multiple tissues, whereas Id4 expression can only be detected in neuronal tissues and in the ventral portion of the epithelium of the developing stomach [15].
• During gastrulation, both Id1 and Id3 are expressed in the tissues derived from the inner cell mass from 5.5 dpc onward, whereas Id2 is expressed in tissues derived from trophoblasts [16].
• Id1 was uniquely expressed in MI/MII spermatocytes undergoing meiotic division [17].
• Embryonic Id1 messages are detected during gastrulation on the proximal side of the embryonic ectoderm, which is the border between the embryo proper and the extraembryonic tissues, and the expression of Id3 is found throughout the entire embryo proper [16].

Associations of Id1 with chemical compounds

• In many cell lineages, bHLH factors are sequestered by members of the Id family, HLH proteins that lack the basic DNA binding domain (Inhibitor of DNA binding proteins (Id-1 to Id-4)) [18].
• Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo [13].
• We have explored the potential regulatory role of the cyclic AMP-dependent signaling pathway on Id gene expression in astroglial primary cultures [19].
• Using wild type and Id1/Id3 heterozygous knockout mice, we analyzed calvarial bone formation in the suture by X-ray picture, proliferation, and mineralization activities of primary calvarial osteoblasts by MTT assay and alizarin red staining and onthotopic in vivo bone formation by BMP injection onto calvaria and micro CT analysis [20].
• Doxorubicin represses the function of the myogenic helix-loop-helix transcription factor MyoD. Involvement of Id gene induction [21].

Physical interactions of Id1

• (iv) Addition of p204 overcame the inhibition by the Id proteins of the binding of MyoD and E47 to DNA in vitro [22].
• The helix-loop-helix protein inhibitor of differentiation and DNA binding (Id-1) is known to promote cellular proliferation in several types of human cancer [23].
• The age-related decrease in E47 DNA-binding does not depend on increased Id inhibitory proteins in bone marrow-derived B cell precursors [24].

Co-localisations of Id1

• In addition, Id colocalizes both spatially and temporally with Hox-7.1, a murine homeobox gene which is associated with regions of high cell proliferation and positional fate assignment [25].

Regulatory relationships of Id1

• Surprisingly, a constitutive overexpression of these Id genes also inhibited osteoblast differentiation initiated by BMP-9 [26].
• Therefore, Id proteins are good candidates for regulating Math1 in the cochlea [27].
• Overexpression of the three Id genes was shown to promote cell proliferation that was coupled with an inhibition of osteogenic differentiation [26].
• Id proteins are believed to block expression of muscle-specific genes by preventing the dimerization between ubiquitous bHLH proteins (E proteins) and myogenic bHLH proteins such as MyoD [28].
• Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1 [29].

Other interactions of Id1

• We therefore propose that the Msx and Id genes are direct target genes of embryonic BMP4 signaling in vivo [30].
• Furthermore, we demonstrated that BMP-9-regulated Id expression is Smad4-dependent [26].
• This loop arose in consequence of it that p204 overcame the inhibition of the synergistic activity of Gata4 and Nkx2.5 by the Id proteins [3].
• As development progresses, the expression of both Id1 and Id3 is detected in the dividing neuroblasts, whereas Id2 and 4 are expressed in presumptive neurons which are undergoing maturation [16].
• In this study, we have analyzed the expression of the dominant negative HLH genes, Id1 to Id4 and the class A gene REB, during Schwann cell development [31].

Analytical, diagnostic and therapeutic context of Id1

• Results from PCR and in situ hybridization indicate that Id1, Id2, and Id3 are expressed within the cochlear duct in a pattern that is consistent with a role in regulation of hair cell development [27].
• Expression of Id helix-loop-helix proteins in colorectal adenocarcinoma correlates with p53 expression and mitotic index [2].
• We have performed a detailed comparative in situ hybridization analysis to examine the patterns of expression of all the members of the Id gene family (Id1-4) during murine gastrulation and neurogenesis [16].
• In contradiction to the previous reports, Northern blot analysis revealed that NGF induces rapid and transient increase of all three Id gene transcriptions [32].
• Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts [33].

References