Id Proteins: Small Molecules, Mighty Regulators

doi:10.1016/B978-0-12-405943-6.00005-1

Current Topics in Developmental Biology

Volume 110, 2014, Pages 189-216

https://doi.org/10.1016/B978-0-12-405943-6.00005-1 Get rights and content

Abstract

The family of inhibitor of differentiation (Id) proteins is a group of evolutionarily conserved molecules, which play important regulatory roles in organisms ranging from Drosophila to humans. Id proteins are small polypeptides harboring a helix-loop-helix (HLH) motif, which are best known to mediate dimerization with other basic HLH proteins, primarily E proteins. Because Id proteins do not possess the basic amino acids adjacent to the HLH motif necessary for DNA binding, Id proteins inhibit the function of E protein homodimers, as well as heterodimers between E proteins and tissue-specific bHLH proteins. However, Id proteins have also been shown to have E protein-independent functions. The Id genes are broadly but differentially expressed in a variety of cell types. Transcription of the Id genes is controlled by transcription factors such as C/EBPβ and Egr as well as by signaling pathways triggered by different stimuli, which include bone morphogenic proteins, cytokines, and ligands of T cell receptors. In general, Id proteins are capable of inhibiting the differentiation of progenitors of different cell types, promoting cell-cycle progression, delaying cellular senescence, and facilitating cell migration. These properties of Id proteins enable them to play significant roles in stem cell maintenance, vasculogenesis, tumorigenesis and metastasis, the development of the immune system, and energy metabolism. In this review, we intend to highlight the current understanding of the function of Id proteins and discuss gaps in our knowledge about the mechanisms whereby Id proteins exert their diverse effects in multiple cellular processes.

Introduction

The inhibitor of differentiation (Id) family of helix-loop-helix (HLH) proteins is a group of evolutionarily conserved molecules, which play important regulatory roles in organisms ranging from Drosophila to humans. Because of their dynamic patterns of expression, the Id family has recently attracted much attention. In this chapter, we will review current advances in our knowledge about the general function of Id proteins and regulation of the Id genes. We will then discuss in broad terms the role of Id proteins in several representative cellular processes.

Section snippets

The Structure and Function of Id Proteins

Mammals have four Id proteins, Id1 to Id4 (Benezra et al., 1990, Christy et al., 1991, Riechmann et al., 1994, Sun et al., 1991), that share extensive sequence homology in the HLH motif (Fig. 5.1A), which mediates the dimerization of Id proteins with basic HLH proteins, primarily the group of E proteins encoded by the E2A (giving rise to E12 and E47), HEB, and E2-2 genes (Massari & Murre, 2000). Because Id proteins do not have the basic amino acids necessary for DNA binding, they serve as

Regulation of Id Gene Expression

The four Id genes are differentially regulated but often have overlapping patterns of expression. Although it is impossible to delineate the regulation of each Id gene in every cell type, the regulation of Id gene has been elucidated in a number of situations, and the general principles obtained are helpful in considering the control of Id gene expression in a specific cell type or under a specific condition of interest. First, several Id genes have been shown to be activated by bone

Id Proteins in Stem Cell Maintenance

Stem cells are defined by their ability to self-renew over the lifetime of an organism and to differentiate into various lineages. Since Id proteins are able to block the activity of E protein transcription factors necessary for development, it seems reasonable that Id proteins would have a function in maintaining stem cells by inhibiting differentiation. This is supported by the fact that expression of Id proteins is typically high in embryonic and adult stem/progenitor cells but levels

Id Proteins in Vasculogenesis

Id1 and Id3 double knockout mice die mid-gestation from multiple cardiac defects and malformation of vasculature, thus highlighting the importance of this group of molecules in vasculogenesis (Lyden et al., 1999, Zhao et al., 2011). The Id1 and Id3 genes share overlapping expression patterns in the cardiovascular system as retaining one of either Id1 or Id3 alleles is sufficient to allow for the survival of Id1^−/−Id3^+/− or Id1^+/−Id3^−/− mice (Lyden et al., 1999). Bone morphogenic proteins are

Id Proteins in Cancer

Id proteins have been implicated in a variety of tumor types either as a driver for tumorigenesis or as an indicator of tumor progression. It is impractical to discuss the role of different Id proteins in every type of tumor. However, it is helpful to examine several general functions of Id proteins in relationship to fundamental processes in cancer biology.

First, the Id1 and Id3 genes are regulated during cell cycle and are generally transcribed in the G1 phase (Barone et al., 1994, Deed et

Id Proteins in the Immune System

The immune system consists of mainly B and T lymphocytes and myeloid lineage cells including macrophages, granulocytes, NK, and dendritic cells. These cells originate from HSCs and initially differentiate in the bone marrow or thymus. Maturation of some of the lineages occurs in peripheral lymphoid organs such as the spleen, lymph nodes, and lymphoid tissues in the intestine. Like the development of other tissues or organs, the generation of immune system involves a series of cell fate choices

Id Proteins in Adipogenesis

Adipocyte differentiation has been shown to be controlled by a series of transcriptional events, and in vitro studies have identified important roles for PPARγ and C/EBPα in the development and maintenance of adipocytes (Barak et al., 1999, Rosen et al., 1999). Hormonal induction of adipogenesis in vitro leads to a transient rise in C/EBPδ and C/EBPβ levels which is followed by an increase in PPARγ expression (Wu et al., 1996, Yeh et al., 1995). PPARγ can then go on to induce C/EBPα expression

Concluding Remarks

Since the discovery of Id proteins over two decades ago, much has been learned about their biological functions. These are highlighted by the ability of Id proteins to delay the onset of cellular senescence, to stimulate cell cycle, and to promote vasculogenesis and angiogenesis, as well as to facilitate cell migration and invasion, all of which make Id proteins important player in tumorigenesis and metastasis. Consistently, increased expression of Id proteins has generally been associated with

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ID3 (inhibitor of DNA binding/differentiation-3) is a transcription factor that enables metastasis by promoting stem cell-like properties in endothelial and tumor cells. The milk thistle flavonolignan silibinin is a phytochemical with anti-metastatic potential through largely unknown mechanisms.
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Analysis of lung cancer patient datasets revealed a top-ranked positive association of ID3 with the BMP9 endothelial receptor ACVRL1/ALK1 and the BMP ligand BMP6. Silibinin treatment blocked the BMP9-induced activation of the ALK1-phospho-SMAD1/5-ID3 axis in brain endothelial cells. Constitutive, acquired, and adaptive expression of ID3 in NSCLC cells were all significantly downregulated in response to silibinin. Silibinin blocked ID3 transcription via BMP-responsive elements in ID3 gene enhancers. Silibinin inhibited the kinase activities of BMPRs in the micromolar range, with the lower IC₅₀ values occurring against ACVRL1/ALK1 and BMPR2. In an in vivo NSCLC xenograft model, tumoral overexpression of ID3 was completely suppressed by systematically achievable oral doses of silibinin.
ID3 is a largely undruggable metastasis-promoting transcription factor. Silibinin is a novel suppressor of ID3 that may be explored as a novel therapeutic approach to interfere with the metastatic dissemination capacity of NSCLC.
Tubuloid differentiation to model the human distal nephron and collecting duct in health and disease
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Organoid technology is rapidly gaining ground for studies on organ (patho)physiology. Tubuloids are long-term expanding organoids grown from adult kidney tissue or urine. The progenitor state of expanding tubuloids comes at the expense of differentiation. Here, we differentiate tubuloids to model the distal nephron and collecting ducts, essential functional parts of the kidney. Differentiation suppresses progenitor traits and upregulates genes required for function. A single-cell atlas reveals that differentiation predominantly generates thick ascending limb and principal cells. Differentiated human tubuloids express luminal NKCC2 and ENaC capable of diuretic-inhibitable electrolyte uptake and enable disease modeling as demonstrated by a lithium-induced tubulopathy model. Lithium causes hallmark AQP2 loss, induces proliferation, and upregulates inflammatory mediators, as seen in vivo. Lithium also suppresses electrolyte transport in multiple segments. In conclusion, this tubuloid model enables modeling of the human distal nephron and collecting duct in health and disease and provides opportunities to develop improved therapies.
Cleavage of semaphorin 4 C interferes with the neuroprotective effect of the semaphorin 4 C/Plexin B2 pathway on experimental intracerebral hemorrhage in rats
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Semaphorin 4 C (SEMA4C) and its cognate receptor Plexin B2 are important regulators of axon guidance and are involved in many neurological diseases, in which SEMA4C acts not only as a ligand ("forward" mode) but also as a signaling receptor ("reverse" mode). However, the role of SEMA4C/Plexin B2 in intracerebral hemorrhage (ICH) remains unclear. In this study, ICH in adult male Sprague-Dawley rats was induced by autologous blood injection in the right basal ganglia. In vitro, cultured primary neurons were subjected to OxyHb to imitate ICH injury. Recombinant SEMA4C (rSEMA4C) and overexpressing lentiviruses encoding full-length SEMA4C or secretory SEMA4C (sSEMA4C) were administered to rats by intraventricular injection. First, we found that elevated levels of sSEMA4C in the cerebrospinal fluid (CSF) of clinical patients were associated with poor prognosis. Both SEMA4C and sSEMA4C were increased in brain tissue around the hematoma after ICH in rats. Overexpression of SEMA4C attenuated neuronal apoptosis, neurosis, and neurologic impairment after ICH. However, treatment with rSEMA4C or sSEMA4C overexpression exacerbated neuronal injury. In addition, when treated with SEMA4C overexpression, the forward mode downstream protein RhoA and the reverse mode downstream ID1/3 transcriptional factors of SEMA4C/Plexin B2 signaling were all activated. Nevertheless, when exposed to rSEMA4C or sSEMA4C overexpression, only the forward mode was activated. Thus, sSEMA4C may be a novel molecular biomarker to predict the prognosis of patients with ICH, and the prevention of SEMA4C cleavage is expected to be a promising therapeutic target.
ID2 inhibits lung adenocarcinoma cell malignant behaviors by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway
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Lung cancer is the most common cancer and one of the main causes of cancer-related deaths, presenting in most cases as metastatic disease. Given the frequent gene mutation and/or signaling deregulation in lung adenocarcinoma, identifying novel factors or agents that target these signaling pathways may be promising strategies for lung adenocarcinoma therapy. Herein, we identified inhibitor of DNA binding 2 (ID2) as an aberrantly downregulated gene in lung adenocarcinoma. ID2 overexpression not only suppressed the viability, colony formation ability, and migration ability of lung adenocarcinoma cells but also decreased the protein levels of N-cadherin, MMP2, MMP9 and the phosphorylation levels of AKT and mTOR. The effects of PI3K/AKT/mTOR signaling agonist on lung adenocarcinoma cells were opposite to those of ID2 overexpression, partially reversing the effects of ID2 overexpression. In these experimental tissue samples, ID2 protein levels and mRNA expression were also down-regulated compared with those in adjacent non-cancerous tissues. Altogether, these findings indicated that ID2 exerts its tumor-suppressive effects on the malignant behavior of lung adenocarcinoma cells by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway. Restoration of ID2 expression in lung adenocarcinoma cells may improve the therapeutic efficacy of lung adenocarcinoma therapies.
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Previously we found that inhibitor of differentiation 3 (Id3) gene, a transcriptional repressor, efficiently inhibits corneal keratocyte differentiation to myofibroblasts in vitro. This study evaluated the potential of adeno-associated virus 5 (AAV5)-mediated Id3 gene therapy to treat corneal scarring using an established rabbit in vivo disease model. Corneal scarring/fibrosis in rabbit eyes was induced by alkali trauma, and 24 h thereafter corneas were administered with either balanced salt solution AAV5-naked vector, or AAV5-Id3 vector (n = 6/group) via an optimized reported method. Therapeutic effects of AAV5-Id3 gene therapy on corneal pathology and ocular health were evaluated with clinical, histological, and molecular techniques. Localized AAV5-Id3 gene therapy significantly inhibited corneal fibrosis/haze clinically from 2.7 to 0.7 on the Fantes scale in live animals (AAV5-naked versus AAV5-Id3; p < 0.001). Furthermore, AAV5-Id3 treatment significantly reduced profibrotic gene mRNA levels: α-smooth muscle actin (α-SMA) (2.8-fold; p < 0.001), fibronectin (3.2-fold; p < 0.001), collagen I (0.8-fold; p < 0.001), and collagen III (1.4-fold; p < 0.001), as well as protein levels of α-SMA (23.8%; p < 0.001) and collagens (1.8-fold; p < 0.001). The anti-fibrotic activity of AAV5-Id3 is attributed to reduced myofibroblast formation by disrupting the binding of E-box proteins to the promoter of α-SMA, a transforming growth factor-β signaling downstream target gene. In conclusion, these results indicate that localized AAV5-Id3 delivery in stroma caused no clinically relevant ocular symptoms or corneal cellular toxicity in the rabbit eyes.
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Chapter Five - Id Proteins: Small Molecules, Mighty Regulators

Abstract

Introduction

Section snippets

The Structure and Function of Id Proteins

Regulation of Id Gene Expression

Id Proteins in Stem Cell Maintenance

Id Proteins in Vasculogenesis

Id Proteins in Cancer

Id Proteins in the Immune System

Id Proteins in Adipogenesis

Concluding Remarks

Molecular Oncology

Journal of Biological Chemistry

Developmental Cell

Molecular Cell

Cell

Blood

European Journal of Cancer

Blood

Immunity

Immunology Letters

Journal of Biological Chemistry

Blood

Immunity

Immunity

Immunity

Journal of Allergy and Clinical Immunology

Immunity

Blood

Blood

Molecular Immunology

Immunity

Molecular Immunology

Journal of Biological Chemistry

Biochemical and Biophysical Research Communications

Cell Stem Cell

Journal of Biological Chemistry

Cancer Cell

Journal of Urology

Journal of Bioliological Chemistry

Blood

Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a

Proceedings of the National Academy of Sciences of United States of America

ID1-, ID2-, and ID3-regulated gene expression in E2A positive or negative prostate cancer cells

Prostate

Non-redundant inhibitor of differentiation (Id) gene expression and function in human prostate epithelial cells

Prostate

Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras- ERK MAPK cascade

Nature Immunology

E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas

Molecular and Cellular Biology

Telomere-independent cellular senescence in human fetal cardiomyocytes

Aging Cell

Id proteins control growth induction in mammalian cells

Proceedings of the National Academy of Sciences of the United States of America

The biology of NKT cells

Annual Review of Immunology

Hematological presentation in systemic lupus erythematosus and its relationship with disease activity

Hematology

Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity

Journal of Experimental Medicine

Angiogenesis as a therapeutic target for obesity and metabolic diseases

Chemical Immunology and Allergy

Id4 promotes senescence and sensitivity to doxorubicin-induced apoptosis in DU145 prostate cancer cells

Anticancer Research

Id-1 induces cell invasiveness in immortalized epithelial cells by regulating cadherin switching and Rho GTPases

Journal of Cellular Biochemistry

An Id-related helix-loop-helix protein encoded by a growth factor-inducible gene

Proceedings of the National Academy of Sciences of the United States of America

Inhibitor of differentiation-3 mediates high fat diet-induced visceral fat expansion

Arteriosclerosis, Thrombosis, and Vascular Biology

Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation

Molecular and Cellular Biology

A novel pathway for mammary epithelial cell invasion induced by the helix-loop-helix protein Id-1

Molecular and Cellular Biology

Id3 is a novel atheroprotective factor containing a functionally significant single-nucleotide polymorphism associated with intima-media thickness in humans

Circulation Research

B-cell aortic homing and atheroprotection depend on Id3

Circulation Research