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Yoshifumi Yokota - One of the best experts on this subject based on the ideXlab platform.

  • ID2 intrinsically regulates lymphoid and erythroid development via interaction with different target proteins
    Blood, 2008
    Co-Authors: Hyung Chan Suh, Yoshifumi Yokota, Kimberly D Klarmann, Jonathan R Keller
    Abstract:

    Inhibitors of DNA binding (Id) family members are key regulators of cellular differentiation and proliferation. These activities are related to the ability of Id proteins to antagonize E proteins and other transcription factors. As negative regulators of E proteins, Id proteins have been implicated in lymphocyte development. Overexpression of Id1, ID2, or Id3 has similar effects on lymphocyte development. However, which Id protein plays a physiologic role during lymphocyte development is not clear. By analyzing ID2 knock-out mice and retroviral transduced hematopoietic progenitors, we demonstrated that ID2 is an intrinsic negative regulator of B-cell development. Hematopoietic progenitor cells overexpressing ID2 did not reconstitute B-cell development in vivo, which resembled the phenotype of E2A null mice. The B-cell population in bone marrow was significantly expanded in ID2 knock-out mice compared with their wild-type littermates. Knock-down of ID2 by shRNA in hematopoietic progenitor cells promoted B-cell differentiation and induced the expression of B-cell lineage–specific genes. These data identified ID2 as a physiologically relevant regulator of E2A during B lymphopoiesis. Furthermore, we identified a novel ID2 function in erythroid development. Overexpression of ID2 enhanced erythroid development, and decreased level of ID2 impaired normal erythroid development. ID2 regulation of erythroid development is mediated via interacting with transcription factor PU.1 and modulating PU.1 and GATA-1 activities. We conclude that ID2 regulates lymphoid and erythroid development via interaction with different target proteins.

  • a molecular pathway including ID2 tbx5 and nkx2 5 required for cardiac conduction system development
    Cell, 2007
    Co-Authors: Ivan P Moskowitz, Jae Bum Kim, Meredith L Moore, Cordula M Wolf, Michael A Peterson, Jay Shendure, Marcelo A Nobrega, Yoshifumi Yokota
    Abstract:

    The cardiac conduction system is an anatomically discrete segment of specialized myocardium that initiates and propagates electrical impulses to coordinate myocardial contraction. To define the molecular composition of the mouse ventricular conduction system we used microdissection and transcriptional profiling by serial analysis of gene expression (SAGE). Conduction-system-specific expression for ID2, a member of the Id gene family of transcriptional repressors, was identified. Analyses of ID2-deficient mice demonstrated structural and functional conduction system abnormalities, including left bundle branch block. A 1.2 kb fragment of the ID2 promoter proved sufficient for cooperative regulation by Nkx2-5 and Tbx5 in vitro and for conduction-system-specific gene expression in vivo. Furthermore, compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and ID2 prevented embryonic specification of the ventricular conduction system. We conclude that a molecular pathway including Tbx5, Nkx2-5, and ID2 coordinates specification of ventricular myocytes into the ventricular conduction system lineage.

  • mature natural killer cell and lymphoid tissue inducing cell development requires ID2 mediated suppression of e protein activity
    Journal of Experimental Medicine, 2007
    Co-Authors: Markus D Boos, Yoshifumi Yokota, Gerard Eberl
    Abstract:

    The ID2 transcriptional repressor is essential for development of natural killer (NK) cells, lymphoid tissue–inducing (LTi) cells, and secondary lymphoid tissues. ID2 was proposed to regulate NK and LTi lineage specification from multipotent progenitors through suppression of E proteins. We report that NK cell progenitors are not reduced in the bone marrow (BM) of ID2 −/− mice, demonstrating that ID2 is not essential for NK lineage specification. Rather, ID2 is required for development of mature (m) NK cells. We define the mechanism by which ID2 functions by showing that a reduction in E protein activity, through deletion of E2A , overcomes the need for ID2 in development of BM mNK cells, LTi cells, and secondary lymphoid tissues. However, mNK cells are not restored in the blood or spleen of ID2 −/− E2A −/− mice, suggesting a role for ID2 in suppression of alternative E proteins after maturation. Interestingly, the few splenic mNK cells in ID2 −/− and ID2 −/− E2A −/− mice have characteristics of thymus-derived NK cells, which develop in the absence of ID2, implying a differential requirement for ID2 in BM and thymic mNK development. Our findings redefine the essential functions of ID2 in lymphoid development and provide insight into the dynamic regulation of E and Id proteins during this process.

  • mature natural killer cell and lymphoid tissue inducing cell development requires ID2 mediated suppression of e protein activity
    Journal of Experimental Medicine, 2007
    Co-Authors: Markus D Boos, Yoshifumi Yokota, Gerard Eberl, Barbara L Kee
    Abstract:

    The ID2 transcriptional repressor is essential for development of natural killer (NK) cells, lymphoid tissue-inducing (LTi) cells, and secondary lymphoid tissues. ID2 was proposed to regulate NK and LTi lineage specification from multipotent progenitors through suppression of E proteins. We report that NK cell progenitors are not reduced in the bone marrow (BM) of ID2(-/-) mice, demonstrating that ID2 is not essential for NK lineage specification. Rather, ID2 is required for development of mature (m) NK cells. We define the mechanism by which ID2 functions by showing that a reduction in E protein activity, through deletion of E2A, overcomes the need for ID2 in development of BM mNK cells, LTi cells, and secondary lymphoid tissues. However, mNK cells are not restored in the blood or spleen of ID2(-/-)E2A(-/-) mice, suggesting a role for ID2 in suppression of alternative E proteins after maturation. Interestingly, the few splenic mNK cells in ID2(-/-) and ID2(-/-)E2A(-/-) mice have characteristics of thymus-derived NK cells, which develop in the absence of ID2, implying a differential requirement for ID2 in BM and thymic mNK development. Our findings redefine the essential functions of ID2 in lymphoid development and provide insight into the dynamic regulation of E and Id proteins during this process.

  • receptor activator of nf κb ligand regulates the proliferation of mammary epithelial cells via ID2
    Molecular and Cellular Biology, 2006
    Co-Authors: Namshik Kim, Yoshifumi Yokota, Hyunju Kim, Bonkyoung Koo, Minchul Kwon, Youngwoong Kim, Yunje Cho, Josef M Penninger, Youngyun Kong
    Abstract:

    Receptor activator of NF-kappaB ligand (RANKL) is a key regulator for mammary gland development during pregnancy. RANKL-deficient mice display impaired development of lobulo-alveolar mammary structures. Similar mammary gland defects have been reported in mice lacking ID2. Here we report that RANKL induces the proliferation of mammary epithelial cells via ID2. RANKL triggers marked nuclear translocation of ID2 in mammary epithelial cells. In vivo studies further demonstrated the defective nuclear translocation of ID2, but the normal expression of cyclin D1, in the mammary epithelial cells of rankl-/- mice. In vitro studies with nuclear localization sequence-tagged ID2 revealed that the nuclear localization of ID2 itself is critical for the downregulation of p21 promoter activity. Moreover, RANKL stimulation failed to induce cell growth and to downregulate p21 expression in ID2-/- mammary epithelial cells. Our results indicate that the inhibitor of helix-loop-helix protein, ID2, is critical to control the proliferation of mammary epithelial cells in response to RANKL stimulation.

Antonio Iavarone - One of the best experts on this subject based on the ideXlab platform.

  • ID2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3f
    Cancer Research, 2010
    Co-Authors: Silvia Coma, Akio Shimizu, Dhara N Amin, Anna Lasorella, Antonio Iavarone
    Abstract:

    Id proteins (Id1 to Id4) are helix-loop-helix transcription factors that promote metastasis. It was found that Semaphorin 3F (SEMA3F), a potent inhibitor of metastasis, was repressed by ID2. High metastatic human tumor cell lines had relatively high amounts of ID2 and low SEMA3F levels compared with their low metastatic counterparts. No correlation between metastatic potential and expression of the other Id family members was observed. Furthermore, ectopic expression of ID2 in low metastatic tumor cells downregulated SEMA3F and, as a consequence, enhanced their ability to migrate and invade, two requisite steps of metastasis in vivo. ID2 overexpression was driven by the c-myc oncoprotein. SEMA3F was a direct target gene of the E47/ID2 pathway. Two E-box sites, which bind E protein transcription factors including E47, were identified in the promoter region of the SEMA3F gene. E47 directly activated SEMA3F promoter activity and expression and promoted SEMA3F biological activities, including filamentous actin depolymerization, inactivation of RhoA, and inhibition of cell migration. Silencing of SEMA3F inhibited the E47-induced SEMA3F expression and biological activities, confirming that these E47-induced effects were SEMA3F dependent. E47 did not induce expression of the other members of the SEMA3 family. ID2, a dominant-negative inhibitor of E proteins, abrogated the E47-induced SEMA3F expression and biological activities. Thus, high metastatic tumor cells overexpress c-myc, leading to upregulation of ID2 expression; the aberrantly elevated amount of ID2 represses SEMA3F expression and, as a consequence, enhances the ability of tumor cells to migrate and invade. Cancer Res; 70(9); 3823–32. ©2010 AACR.

  • degradation of ID2 by the anaphase promoting complex couples cell cycle exit and axonal growth
    Nature, 2006
    Co-Authors: Anna Lasorella, Judith Stegmuller, Daniele Guardavaccaro, Maria Stella Carro, Gerson Rothschild, Luis De La Torreubieta, Michele Pagano, Azad Bonni, Antonio Iavarone
    Abstract:

    The anaphase-promoting complex/cyclosome (APC/C) has a key role in controlling mitosis. This paper identifies ID2 as a target of the APC/C that is responsible for its function in regulating axonal growth. In the developing nervous system, ID2 (inhibitor of DNA binding 2, also known as inhibitor of differentiation 2) enhances cell proliferation, promotes tumour progression and inhibits the activity of neurogenic basic helix–loop–helix (bHLH) transcription factors1,2. The anaphase promoting complex/cyclosome and its activator Cdh1 (APC/CCdh1) restrains axonal growth but the targets of APC/CCdh1 in neurons are unknown3,4,5. ID2 and other members of the Id family are very unstable proteins that are eliminated as cells enter the quiescent state, but how they are targeted for degradation has remained elusive6,7. Here we show that ID2 interacts with the core subunits of APC/C and Cdh1 in primary neurons. APC/CCdh1 targets ID2 for degradation through a destruction box motif (D box) that is conserved in Id1 and Id4. Depletion of Cdh1 stabilizes Id proteins in neurons, whereas ID2 D-box mutants are impaired for Cdh1 binding and remain stable in cells that exit from the cell cycle and contain active APC/CCdh1. Mutants of the ID2 D box enhance axonal growth in cerebellar granule neurons in vitro and in the context of the cerebellar cortex, and overcome the myelin inhibitory signals for growth. Conversely, activation of bHLH transcription factors induces a cluster of genes with potent axonal inhibitory functions including the gene coding for the Nogo receptor, a key transducer of myelin inhibition. Degradation of ID2 in neurons permits the accumulation of the Nogo receptor, thereby linking APC/CCdh1 activity with bHLH target genes for the inhibition of axonal growth. These findings indicate that deregulated Id activity might be useful to reprogramme quiescent neurons into the axonal growth mode.

  • degradation of ID2 by the anaphase promoting complex couples cell cycle exit and axonal growth
    Nature, 2006
    Co-Authors: Anna Lasorella, Judith Stegmuller, Daniele Guardavaccaro, Maria Stella Carro, Gerson Rothschild, Luis De La Torreubieta, Michele Pagano, Azad Bonni, Guangchao Liu, Antonio Iavarone
    Abstract:

    In the developing nervous system, ID2 (inhibitor of DNA binding 2, also known as inhibitor of differentiation 2) enhances cell proliferation, promotes tumour progression and inhibits the activity of neurogenic basic helix-loop-helix (bHLH) transcription factors. The anaphase promoting complex/cyclosome and its activator Cdh1 (APC/C(Cdh1)) restrains axonal growth but the targets of APC/C(Cdh1) in neurons are unknown. ID2 and other members of the Id family are very unstable proteins that are eliminated as cells enter the quiescent state, but how they are targeted for degradation has remained elusive. Here we show that ID2 interacts with the core subunits of APC/C and Cdh1 in primary neurons. APC/C(Cdh1) targets ID2 for degradation through a destruction box motif (D box) that is conserved in Id1 and Id4. Depletion of Cdh1 stabilizes Id proteins in neurons, whereas ID2 D-box mutants are impaired for Cdh1 binding and remain stable in cells that exit from the cell cycle and contain active APC/C(Cdh1). Mutants of the ID2 D box enhance axonal growth in cerebellar granule neurons in vitro and in the context of the cerebellar cortex, and overcome the myelin inhibitory signals for growth. Conversely, activation of bHLH transcription factors induces a cluster of genes with potent axonal inhibitory functions including the gene coding for the Nogo receptor, a key transducer of myelin inhibition. Degradation of ID2 in neurons permits the accumulation of the Nogo receptor, thereby linking APC/C(Cdh1) activity with bHLH target genes for the inhibition of axonal growth. These findings indicate that deregulated Id activity might be useful to reprogramme quiescent neurons into the axonal growth mode.

  • the protein enh is a cytoplasmic sequestration factor for ID2 in normal and tumor cells from the nervous system
    Proceedings of the National Academy of Sciences of the United States of America, 2006
    Co-Authors: Anna Lasorella, Antonio Iavarone
    Abstract:

    ID2 is a natural inhibitor of the basic helix–loop–helix transcription factors and the retinoblastoma tumor suppressor protein. Active ID2 prevents differentiation and promotes cell-cycle progression and tumorigenesis in the nervous system. A key event that regulates ID2 activity during differentiation is translocation from the nucleus to the cytoplasm. Here we show that the actin-associated protein enigma homolog (ENH) is a cytoplasmic retention factor for ID2. ENH contains three LIM domains, which bind to the helix–loop–helix domain of Id proteins in vitro and in vivo. ENH is up-regulated during neural differentiation, and its ectopic expression in neuroblastoma cells leads to translocation of ID2 from the nucleus to the cytoplasm, with consequent inactivation of transcriptional and cell-cycle-promoting functions of ID2. Conversely, silencing of ENH by RNA interference prevents cytoplasmic relocation of ID2 in neuroblastoma cells differentiated with retinoic acid. Finally, the differentiated neural crest-derived tumor ganglioneuroblastoma coexpresses ID2 and ENH in the cytoplasm of ganglionic cells. These data indicate that ENH contributes to differentiation of the nervous system through cytoplasmic sequestration of ID2. They also suggest that ENH is a restraining factor of the oncogenic activity of Id proteins in neural tumors.

  • ID2 mediates tumor initiation proliferation and angiogenesis in rb mutant mice
    Molecular and Cellular Biology, 2005
    Co-Authors: Anna Lasorella, Yoshifumi Yokota, Robert G Russell, Gerson Rothschild, Antonio Iavarone
    Abstract:

    The inhibitor of differentiation ID2 is a target of the retinoblastoma (Rb) protein during mouse embryogenesis. In Rb+/− mice, LOH at the wild-type Rb allele initiates pituitary adenocarcinoma, a tumor derived from embryonic melanotropes. Here we identify a critical role for ID2 in initiation, growth, and angiogenesis of pituitary tumors from Rb+/− mice. We show that proliferation and differentiation are intimately coupled in Rb+/− pituitary cells before tumor initiation. In ID2-null pituitaries, premature activation of basic helix-loop-helix-mediated transcription and expression of the cdk inhibitor p27Kip1 impairs the proliferation of melanotropes and tumor initiation. Without ID2, Rb+/− mice have fewer early tumor lesions and a markedly decreased proliferation rate of the tumor foci. Expression of ID2 by pituitary tumor cells promotes growth and angiogenesis by functioning as a master regulator of vascular endothelial growth factor (VEGF). In human neuroblastoma, the N-Myc-driven expression of ID2 is sufficient and necessary for expression of VEGF. These results establish that aberrant ID2 activity directs initiation and progression of embryonal cancer.

Anna Lasorella - One of the best experts on this subject based on the ideXlab platform.

  • transcription factor ID2 prevents e proteins from enforcing a naive t lymphocyte gene program during nk cell development
    Science immunology, 2018
    Co-Authors: Erin C Zook, Anna Lasorella, Mikael Sigvardsson, Renee F De Pooter, Mihalis Verykokakis, Aimee M Beaulieu, Mark Maienscheincline, Joseph C Sun, Barbara L Kee
    Abstract:

    All innate lymphoid cells (ILCs) require the small helix-loop-helix transcription factor ID2, but the functions of ID2 are not well understood in these cells. We show that mature natural killer (NK) cells, the prototypic ILCs, developed in mice lacking ID2 but remained as precursor CD27 + CD11b − cells that failed to differentiate into CD27 − CD11b + cytotoxic effectors. We show that ID2 limited chromatin accessibility at E protein binding sites near naive T lymphocyte–associated genes including multiple chemokine receptors, cytokine receptors, and signaling molecules and altered the NK cell response to inflammatory cytokines. In the absence of ID2, CD27 + CD11b − NK cells expressed ID3, a helix-loop-helix protein associated with naive T cells, and they transitioned from a CD8 memory precursor–like to a naive-like chromatin accessibility state. We demonstrate that ID3 was required for the development of ID2-deficient NK cells, indicating that completely unfettered E protein function is incompatible with NK cell development. These data solidify the roles of ID2 and ID3 as mediators of effector and naive gene programs, respectively, and revealed a critical role for ID2 in promoting a chromatin state and transcriptional program in CD27 + CD11b − NK cells that supports cytotoxic effector differentiation and cytokine responses.

  • ID2 reinforces th1 differentiation and inhibits e2a to repress tfh differentiation
    Nature Immunology, 2016
    Co-Authors: Laura A Shaw, Anna Lasorella, Simon Belanger, Kyla D Omilusik, Sunglim Cho, James P Scottbrowne, Philip J Nance, John Goulding, Shane Crotty
    Abstract:

    The differentiation of helper T cells into effector subsets is critical to host protection. Transcription factors of the E-protein and Id families are important arbiters of T cell development, but their role in the differentiation of the TH1 and TFH subsets of helper T cells is not well understood. Here, TH1 cells showed more robust ID2 expression than that of TFH cells, and depletion of ID2 via RNA-mediated interference increased the frequency of TFH cells. Furthermore, TH1 differentiation was blocked by ID2 deficiency, which led to E-protein-dependent accumulation of effector cells with mixed characteristics during viral infection and severely impaired the generation of TH1 cells following infection with Toxoplasma gondii. The TFH cell-defining transcriptional repressor Bcl6 bound the ID2 locus, which provides a mechanism for the bimodal ID2 expression and reciprocal development of TH1 cells and TFH cells.

  • innate lymphoid cells control early colonization resistance against intestinal pathogens through ID2 dependent regulation of the microbiota
    Immunity, 2015
    Co-Authors: Anna Lasorella, Xiaohuan Guo, Yong Liang, Yuan Zhang, Barbara L Kee
    Abstract:

    Microbiota-mediated effects on the host immune response facilitate colonization resistance against pathogens. However, it is unclear whether and how the host immune response can regulate the microbiota to mediate colonization resistance. ID2, an essential transcriptional regulator for the development of innate lymphoid cell (ILC) progenitors, remains highly expressed in differentiated ILCs with unknown function. Using conditionally deficient mice in which ID2 is deleted from differentiated ILC3s, we observed that these mutant mice exhibited greatly impaired gut colonization resistance against Citrobacter rodentium. Utilizing gnotobiotic hosts, we showed that the ID2-dependent early colonization resistance was mediated by interleukin-22 (IL-22) regulation of the microbiota. In addition to regulating development, ID2 maintained homeostasis of ILC3s and controlled IL-22 production through an aryl hydrocarbon receptor (AhR) and IL-23 receptor pathway. Thus, ILC3s can mediate immune surveillance, which constantly maintains a proper microbiota, to facilitate early colonization resistance through an ID2-dependent regulation of IL-22.

  • eto family protein mtg16 regulates the balance of dendritic cell subsets by repressing ID2
    Journal of Experimental Medicine, 2014
    Co-Authors: Hiyaa S Ghosh, Anna Lasorella, Michele Ceribelli, Ines Matos, Allan Lazarovici, Harmen J Bussemaker, Scott W Hiebert, Kang Liu, Louis M Staudt, Boris Reizis
    Abstract:

    Dendritic cells (DCs) comprise two major subsets, the interferon (IFN)-producing plasmacytoid DCs (pDCs) and antigen-presenting classical DCs (cDCs). The development of pDCs is promoted by E protein transcription factor E2-2, whereas E protein antagonist ID2 is specifically absent from pDCs. Conversely, ID2 is prominently expressed in cDCs and promotes CD8+ cDC development. The mechanisms that control the balance between E and Id proteins during DC subset specification remain unknown. We found that the loss of Mtg16, a transcriptional cofactor of the ETO protein family, profoundly impaired pDC development and pDC-dependent IFN response. The residual Mtg16-deficient pDCs showed aberrant phenotype, including the expression of myeloid marker CD11b. Conversely, the development of cDC progenitors (pre-DCs) and of CD8+ cDCs was enhanced. Genome-wide expression and DNA-binding analysis identified ID2 as a direct target of Mtg16. Mtg16-deficient cDC progenitors and pDCs showed aberrant induction of ID2, and the deletion of ID2 facilitated the impaired development of Mtg16-deficient pDCs. Thus, Mtg16 promotes pDC differentiation and restricts cDC development in part by repressing ID2, revealing a cell-intrinsic mechanism that controls subset balance during DC development.

  • ID2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3f
    Cancer Research, 2010
    Co-Authors: Silvia Coma, Akio Shimizu, Dhara N Amin, Anna Lasorella, Antonio Iavarone
    Abstract:

    Id proteins (Id1 to Id4) are helix-loop-helix transcription factors that promote metastasis. It was found that Semaphorin 3F (SEMA3F), a potent inhibitor of metastasis, was repressed by ID2. High metastatic human tumor cell lines had relatively high amounts of ID2 and low SEMA3F levels compared with their low metastatic counterparts. No correlation between metastatic potential and expression of the other Id family members was observed. Furthermore, ectopic expression of ID2 in low metastatic tumor cells downregulated SEMA3F and, as a consequence, enhanced their ability to migrate and invade, two requisite steps of metastasis in vivo. ID2 overexpression was driven by the c-myc oncoprotein. SEMA3F was a direct target gene of the E47/ID2 pathway. Two E-box sites, which bind E protein transcription factors including E47, were identified in the promoter region of the SEMA3F gene. E47 directly activated SEMA3F promoter activity and expression and promoted SEMA3F biological activities, including filamentous actin depolymerization, inactivation of RhoA, and inhibition of cell migration. Silencing of SEMA3F inhibited the E47-induced SEMA3F expression and biological activities, confirming that these E47-induced effects were SEMA3F dependent. E47 did not induce expression of the other members of the SEMA3 family. ID2, a dominant-negative inhibitor of E proteins, abrogated the E47-induced SEMA3F expression and biological activities. Thus, high metastatic tumor cells overexpress c-myc, leading to upregulation of ID2 expression; the aberrantly elevated amount of ID2 represses SEMA3F expression and, as a consequence, enhances the ability of tumor cells to migrate and invade. Cancer Res; 70(9); 3823–32. ©2010 AACR.

Mark A Israel - One of the best experts on this subject based on the ideXlab platform.

  • ID2 promotes survival of glioblastoma cells during metabolic stress by regulating mitochondrial function
    Cell Death and Disease, 2017
    Co-Authors: Zhonghua Zhang, Matthew C Havrda, Gilbert J Rahme, Pranam D Chatterjee, Mark A Israel
    Abstract:

    Tumor cells proliferate in cellular environments characterized by a lack of optimal tissue organization resulting oftentimes in compromised cellular metabolism affecting nutrition, respiration, and energetics. The response of tumor cells to adverse environmental conditions is a key feature affecting their pathogenicity. We found that inhibitor of DNA binding 2 (ID2) expression levels significantly correlate with the ability of glioblastoma (GBM)-derived cell lines to survive glucose deprivation. ID2 suppressed mitochondrial oxidative respiration and mitochondrial ATP production by regulating the function of mitochondrial electron transport chain (mETC) complexes, resulting in reduced superoxide and reactive oxygen species (ROS) production from mitochondria. ID2 suppression of ROS production reduced mitochondrial damage and enhanced tumor cell survival during glucose deprivation. Bioinformatics analysis of GBM gene expression data from The Cancer Genome Atlas (TCGA) database revealed that expression of ID2 mRNA is unique among ID gene family members in correlating with the expression of nuclear genes involved in mitochondrial energy metabolism and assembly of mETC. Our data indicate that the expression level of ID2 in GBM cells can predict the sensitivity of GBM-derived tumor cells to decreased glucose levels. Low levels of ID2 expression in human GBM tissues may identify a clinical group in which metabolic targeting of glycolytic pathways can be expected to have the greatest therapeutic efficacy.

  • abstract 2128 phosphorylation of ID2 at the n terminus modulates ID2 degradation and mediates cell cycle regulation in neural progenitor cells
    Cancer Research, 2015
    Co-Authors: Jaclyn Sullivan, Matthew C Havrda, Brenton R Paolella, Arminja N Kettenbach, Scott A Gerber, Mark A Israel
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Glioblastoma is the most common and aggressive type of primary brain tumor in adults with more than 14,000 new cases diagnosed each year in the US. Although surgical resection, radiation, and cytotoxic therapies are available these current treatment methods are not curative and the median survival of patients remains at 12-15 months. Inhibitor of DNA binding proteins (Id1-Id4) are a family of genetically encoded dominant negative regulators of basic helix-loop-helix (bHLH) transcription factors. Id proteins are widely reported to inhibit differentiation and promote cell cycle transit in neural progenitor cells (NPCs) and have been implicated in the development of glioma. Our laboratory has observed a poor correlation between ID2 mRNA levels and ID2 protein levels in multiple cell types which led us to seek post-translational modifications that effected steady state ID2 protein levels and key ID2 mediated cellular functions. Using mass spectrometry we have identified three phosphorylation sites within the N-terminus of ID2 in proliferating NPCs. To interrogate the importance of ID2 N-terminal phosphorylation, ID2-/- NPCs were modified to express WT ID2 or various ID2 mutants expressing proteins that could not be phosphorylated at the N-terminus. We observed that NPCs expressing these mutants had higher steady state levels of ID2 than NPCs expressing WT ID2. It is known that WT ID2 is rapidly degraded by the proteasome. However, when proliferating NPCs were treated with cyclohexamide, phospho-ablated ID2 molecules exhibited a longer half-life than WT ID2 molecules indicating that loss of N-terminal phosphorylation results in resistance to proteasome-mediated degradation. Moreover, NPCs expressing this degradation-resistant, phospho-ablated ID2 protein proliferate more rapidly than NPCs expressing WT ID2, a finding consistent with the well-characterized function of ID2 in driving proliferation. Seeking to identify molecules whose inhibition might enhance ID2 phosphorylation, we evaluated the activity of multiple phosphatase inhibitors and identified phosphatases that could potentially function to stabilize pro-proliferative ID2 in NPCs. Calyculin A treatment caused a significant loss of ID2 protein suggesting that the PP1, PP2A, PP4 and/or PP6 phosphatases were likely regulators of ID2. To complement these pharmacologic studies we used a genetic approach to decrease PP2A expression and found that ID2 protein levels were decreased. Our findings indicate that inhibition of this phosphatase may provide a novel mechanism to decrease ID2 protein levels by causing rapid degradation of ID2. Citation Format: Jaclyn Sullivan, Matthew Havrda, Brenton Paolella, Arminja Kettenbach, Scott Gerber, Mark A. Israel. Phosphorylation of ID2 at the N-terminus modulates ID2 degradation and mediates cell cycle regulation in neural progenitor cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2128. doi:10.1158/1538-7445.AM2015-2128

  • abstract 1402 regulation of ID2 in the proliferation of glioma initiating neural progenitor cells
    Cancer Research, 2014
    Co-Authors: Jaclyn Sullivan, Matthew C Havrda, Brenton R Paolella, Arminja N Kettenbach, Scott A Gerber, Mark A Israel
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA There are more than 14,000 new cases of malignant high grade glioma diagnosed each year in the US, and although surgical resection, radiation, and cytotoxic therapies are available, these current treatment methods are not curative. Inhibitor of DNA Binding 2 (ID2), a helix-loop-helix (HLH) protein, functions as a dominant negative inhibitor of basic helix-loop-helix (bHLH) transcription factors and is highly expressed in glioma. Recent data from our laboratory defines a critical role for ID2 in the pathogenesis of a subset of glioma known as proneural glioma. ID2 protein function has been characterized in neural progenitor cells (NPCs) where it acts to suppress differentiation and enhance cell cycle progression. These are two key characteristics that are shared with glioma-derived stem cells. We have identified three phosphorylation sites on ID2 in proliferating NPCs using mass spectrometry, and prepared altered ID2 molecules that cannot be phosphorylated at each of these sites. ID2-/- NPCs expressing WT and phosphorylation-site-ablated ID2 have been prepared to examine the role of ID2 phosphorylation in mediating its interactions with binding partners and in modulating the rate of proteasome-dependent degradation. We found an increased level of ID2 in NPCs expressing a mutant form of ID2 that cannot by phosphorylated when compared with NPCs expressing WT ID2. Moreover, the level of WT ID2 protein decreases when NPCs exit the cell cycle; however, unphosphorylated ID2 resists this degradation and exhibits a longer half-life. Stable isotope labeling by amino acids in cell culture (SILAC) experiments revealed that unphosphorylated ID2 molecules bind significantly less than WT ID2 to several anaphase promoting complex (APC) subunits. These findings suggested a possible mechanism for phosphorylation-dependent proteasome-mediated degradation of ID2 in NPCs. Understanding the effect of ID2 phosphorylation in modulating steady state levels of this important protein will inform future studies designed to identify pathways of interest in the transformation of NPCs and the malignant progression of NPC-initiated glioma. This work was supported in part by the Theodora B. Betz Foundation. Citation Format: Jaclyn Sullivan, Matthew Havrda, Brenton Paolella, Arminja Kettenbach, Scott Gerber, Mark A. Israel. Regulation of ID2 In the proliferation of glioma-initiating neural progenitor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1402. doi:10.1158/1538-7445.AM2014-1402

  • elevated ID2 expression results in precocious neural stem cell depletion and abnormal brain development
    Stem Cells, 2013
    Co-Authors: Hee Jung Park, Mark A Israel, Mingi Hong, Roderick T Bronson, Wayne N Frankel, Kyuson Yun
    Abstract:

    ID2 is a helix-loop-helix (HLH) transcription factor essential for normal development and its expression is dysregulated in many human neurological conditions. Although it is speculated that elevated ID2 levels contribute to the pathogenesis of these disorders, it is unknown whether dysregulated ID2 expression is sufficient to perturb normal brain development or function. Here, we show that mice with elevated ID2 expression during embryonic stages develop microcephaly, and that females in particular are prone to generalized tonic-clonic seizures. Analyses of ID2 transgenic brains indicate that ID2 activity is highly cell context specific: elevated ID2 expression in naive NSCs in early neuroepithelium induces apoptosis and loss of NSCs and intermediate progenitors. Activation of ID2 in maturing neuroepithelium results in less severe phenotypes and is accompanied by elevation of G1 Cyclin expression and p53 target gene expression. In contrast, activation of ID2 in committed intermediate progenitors has no significant phenotype. Functional analysis with ID2 over-expressing and ID2-null NSCs shows that ID2 negatively regulates NSC self-renewal in vivo, in contrast to previous cell culture experiments. Deletion of p53 function from ID2-transgenic brains rescues apoptosis and results in increased incidence of brain tumors. Furthermore, ID2 over-expression normalizes the increased self-renewal of p53-null NSCs, suggesting that ID2 activates and modulates the p53 pathway in NSCs. Together, these data suggest that elevated ID2 expression in embryonic brains can cause deregulated NSC self-renewal, differentiation and survival that manifest in multiple neurological outcomes in mature brains, including microcephaly, seizures, and brain tumors.

  • p53 directly represses ID2 to inhibit the proliferation of neural progenitor cells
    Stem Cells, 2011
    Co-Authors: Brenton R Paolella, Matthew C Havrda, Akio Mantani, Christina M Wray, Zhonghua Zhang, Mark A Israel
    Abstract:

    Neural progenitor cells (NPCs) have the capacity to proliferate and give rise to all major central nervous system cell types and represent a possible cell of origin in gliomagenesis. Deletion of the tumor suppressor gene Tp53 (p53) results in increased proliferation and self-renewal of NPCs and is a common genetic mutation found in glioma. We have identified inhibitor of DNA binding 2 (ID2) as a novel target gene directly repressed by p53 to maintain normal NPC proliferation. p53((-/-)) NPCs express elevated levels of ID2 and suppression of ID2 expression is sufficient to inhibit the increased proliferation and self-renewal which results from p53 loss. Elevated expression of ID2 in wild-type NPCs phenocopies the behavior of p53((-/-)) NPCs by enhancing NPC proliferation and self-renewal. Interestingly, p53 directly binds to a conserved site within the ID2 promoter to mediate these effects. Finally, we have identified elevated ID2 expression in glioma cell lines with mutated p53 and demonstrated that constitutive expression of ID2 plays a key role in the proliferation of glioma stem-like cells. These findings indicate that ID2 functions as a proproliferative gene that antagonizes p53-mediated cell cycle regulation in NPCs and may contribute to the malignant proliferation of glioma-derived tumor stem cells.

Qingyin Zheng - One of the best experts on this subject based on the ideXlab platform.

  • hearing loss in id1 id3 and id1 id3 mice is associated with a high incidence of middle ear infection otitis media
    Frontiers in Genetics, 2021
    Co-Authors: Qingyin Zheng, Tihua Zheng, Aizhen Zhang, Bin Yan, Zhaoqiang Zhang, Yan Zhang
    Abstract:

    Inhibitors of differentiation/DNA binding (Id) proteins are crucial for inner ear development, but whether Id mutations affect middle ear function remains unknown. In this study, we obtained Id1-/-; Id3+/- mice and Id1+/-; Id3-/- mice and carefully examined their middle ear morphology and auditory function. Our study revealed a high incidence (>50%) of middle ear infection in the compound mutant mice. These mutant mice demonstrated hearing impairment starting around 30 days of age, as the mutant mice presented elevated auditory brainstem response (ABR) thresholds compared to those of the littermate controls. The distortion product of otoacoustic emission (DPOAE) was also used to evaluate the conductive function of the middle ear, and we found much lower DPOAE amplitudes in the mutant mice, suggesting sound transduction in the mutant middle ear is compromised. This is the first study of the middle ears of Id compound mutant mice, and high incidence of middle ear infection determined by otoscopy and histological analysis of middle ear suggests that Id1/Id3 compound mutant mice are a novel model for human otitis media (OM).

  • Image_1_Hearing Loss in Id1−/−; Id3+/− and Id1+/−; Id3−/− Mice Is Associated With a High Incidence of Middle Ear Infection (Otitis Media).TIF
    'Frontiers Media SA', 2021
    Co-Authors: Qingyin Zheng, Tihua Zheng, Aizhen Zhang, Bin Yan, Zhaoqiang Zhang, Yan Zhang
    Abstract:

    Inhibitors of differentiation/DNA binding (Id) proteins are crucial for inner ear development, but whether Id mutations affect middle ear function remains unknown. In this study, we obtained Id1−/−; Id3+/− mice and Id1+/−; Id3−/− mice and carefully examined their middle ear morphology and auditory function. Our study revealed a high incidence (>50%) of middle ear infection in the compound mutant mice. These mutant mice demonstrated hearing impairment starting around 30 days of age, as the mutant mice presented elevated auditory brainstem response (ABR) thresholds compared to those of the littermate controls. The distortion product of otoacoustic emission (DPOAE) was also used to evaluate the conductive function of the middle ear, and we found much lower DPOAE amplitudes in the mutant mice, suggesting sound transduction in the mutant middle ear is compromised. This is the first study of the middle ears of Id compound mutant mice, and high incidence of middle ear infection determined by otoscopy and histological analysis of middle ear suggests that Id1/Id3 compound mutant mice are a novel model for human otitis media (OM).