Disease relevance of Id3

• 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].
• Id1 and Id3 genes are required for vascularization, growth, and metastasis of xenograft tumors [2].
• Id1 and Id3 were strongly expressed in the endothelial cells of poorly differentiated prostate adenocarcinoma but not in the vasculature of well-differentiated tumors, a finding that is corroborated in human prostate tumor samples [2].
• A T cell intrinsic role of Id3 in a mouse model for primary Sjogren's syndrome [3].
• Thus, this study establishes a critical connection between Id3-mediated T cell development and autoimmune diseases [3].

Psychiatry related information on Id3

• Id3, a member of the Id multigene family of dominant negative helix-loop-helix transcription factors, is induced sharply in murine fibroblasts by serum growth factors [4].

High impact information on Id3

• This review summarizes the current data and examines the various functions of E proteins and their antagonists, Id2 and Id3, throughout lymphoid maturation [5].
• The Id1-Id3 double knockout mice also display vascular malformations in the forebrain and an absence of branching and sprouting of blood vessels into the neuroectoderm [6].
• Id3(-/-) mice were found to have autoantibodies, lymphocytic infiltrates in, and decreased secretion by exocrine glands [7].
• Blimp-1 initiated this cascade of gene expression changes by directly repressing genes encoding several transcription factors, including Spi-B and Id3, that regulate signaling by the B cell receptor [8].
• Finally, we show that E2A and Id3 interact genetically to regulate thymocyte development [9].

Chemical compound and disease context of Id3

• 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 [10].

Biological context of Id3

• 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 [11].
• Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function [12].
• Overexpression of Id3 efficiently inhibited the MyoD-mediated activation of the muscle-specific creatine kinase (MCK) reporter gene [12].
• On the basis of these data, it is speculated that CSN-mediated phosphorylation inhibits ubiquitination of Id1 and Id3 [13].
• Expression of the helix-loop-helix gene Id3 during murine embryonic development [14].

Anatomical context of Id3

• Consistent with its putative role as an inhibitor of differentiation, Id3 mRNA was detected in proliferating skeletal muscle cells, was further induced by basic fibroblast growth factor (bFGF) and was down-regulated in differentiated muscle cultures [12].
• The inhibitors of CSN associated kinases, curcumin and emodin, significantly induce ubiquitination and proteasome-dependent degradation of transiently expressed Id3 in HeLa cells [13].
• We have investigated the potential role of Id3 in the control of muscle cell differentiation [15].
• Id3 mRNA is expressed at a high level in proliferating myoblasts and is down-regulated following induction of differentiation [15].
• Id3 transcripts are present throughout embryogenesis and are found in neural cells as well as in cartilage primordia and in epithelial cells lining a variety of organs [16].

Associations of Id3 with chemical compounds

• 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 [17].
• Further analysis of lymphocytes isolated from Id3-deficient mice reveals a B-cell defect in their proliferation response to BCR cross-linking but not to lipopolysaccharide or a combination of BCR cross-linking and interleukin-4 [18].
• We here demonstrated that there was a dramatic rise of Id2 and Id3 mRNA levels when 3T3-L1 adipocytes or isolated rat fat cells were exposed to lipolytic and anti-lipogenic agents, forskolin and isoproterenol [19].
• The role of NAD(P)H oxidase in the regulation of a subset of these genes (CD44, BMP4, Id1, and Id3) was confirmed using modulators of reactive oxygen species (ROS) generation, a ROS scavenger and in gain-of-function experiments [20].
• Glucose and other insulin secretagogues induce, rather than inhibit, expression of Id-1 and Id-3 in pancreatic islet beta cells [10].

Physical interactions of Id3

• Additional far Western and pull-down studies with Id3 support our two-hybrid data and show that the transcription regulator can bind to CSN5 and CSN7 [13].
• However, stimuli that mimic pre-T cell receptor (TCR) signaling in committed T cell precursors inhibit E47 DNA-binding activity and induce the bHLH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependent pathway [21].

Regulatory relationships of Id3

• Finally, we show by in situ hybridization that the Id3 mRNA is co-expressed with the myogenic regulatory factor myogenin in somites and developing muscle during embryogenesis, although unlike the myogenic regulatory factors, Id3 is also expressed in many other locations in the embryo [15].
• In conclusion, these data demonstrate that BMP-7 antagonizes the TGF-beta1-dependent fibrogenic activity of mouse pulmonary myofibroblastic cells by inducing Id2 and Id3 [22].
• Significant increases in TNF alpha-induced Id2 and Id3 mRNA were observed in the ventricular/subventricular zone, cingulum and corpus callosum [23].

Other interactions of Id3

• Here we report that Id1, Id2, and Id3 are induced shortly after serum stimulation in arrested NIH 3T3 [24].
• Within the detection limits of in situ hybridization, Id4 and Id3 expression is mutually exclusive in neural precursor cells of the developing brain, suggesting distinct regulatory functions for these dnHLH proteins during neurogenesis [16].
• Chimeric protein containing the N-terminal region of Id3 and the C-terminus of Id2 was also non-functional in transfected cells [12].
• Furthermore, previous experiments suggested a mutually exclusive expression of the proto-oncogene N-myc an Id3 [14].
• Curcumin increased Id3-ubiquitin conjugate formation, as shown by Western blotting and His-pull-downs [13].

Analytical, diagnostic and therapeutic context of Id3

• Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts [6].
• Adoptive transfer experiment indicated a T cell intrinsic role for Id3 in the development of Sjogren's symptoms [3].
• Furthermore, genetic ablation of T cells or neonatal 3 day thymectomy in Id3-deficient mice showed a rescue of disease symptoms, suggesting a thymic origin of autoimmune T cells [3].
• Constitutive expression of Id3 completely blocks development of CD34+ cells into T cells in a fetal thymic organ culture (FTOC) [25].

References