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Antonio Iavarone - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulator id2 is required for the cd4 t cell immune response in the development of experimental autoimmune encephalomyelitis
Journal of Immunology, 2012Co-Authors: Yenyu Lin, Anna Lasorella, Antonio Iavarone, Mary Elizabeth Jonesmason, Makoto Inoue, Mari L Shinohara, Yuan ZhuangAbstract:An effective immune response to Ag challenge is critically dependent on the size of the effector cell population generated from clonal activation of Ag-specific T cells. The transcription network involved in regulating the size of the effector population, particularly for CD4 Th cells, is poorly understood. In this study, we investigate the role of Id2, an inhibitor of E protein transcription factors, in the generation of CD4 effectors. Using a T cell-specific conditional Id2 knockout mouse model, we show that inhibitor of DNA binding (Id)2 is essential for the development of experimental autoimmune encephalomyelitis. Although Ag-specific and IL-17–producing CD4 T cells are produced in these mice, the activated CD4 T cells form a smaller pool of effector cells in the peripheral lymphoid organs, exhibit reduced proliferation and increased cell death, and are largely absent in the CNS. In the absence of Id2, E protein targets, including the proapoptotic protein Bim and SOCS3, are expressed at higher levels among activated CD4 T cells. This study reveals a critical role of Id2 in the control of effector CD4 T cell population size and the development of a Th17-mediated autoimmune disease.
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id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3f
Cancer Research, 2010Co-Authors: Dhara N Amin, Akio Shimizu, Anna Lasorella, Antonio IavaroneAbstract: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.
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degradation of id2 by the anaphase promoting complex couples cell cycle exit and axonal growth
Nature, 2006Co-Authors: Anna Lasorella, Judith Stegmuller, Daniele Guardavaccaro, Maria Stella Carro, Gerson Rothschild, Luis De La Torreubieta, Michele Pagano, Azad Bonni, Antonio IavaroneAbstract: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.
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degradation of id2 by the anaphase promoting complex couples cell cycle exit and axonal growth
Nature, 2006Co-Authors: Anna Lasorella, Judith Stegmuller, Daniele Guardavaccaro, Maria Stella Carro, Gerson Rothschild, Luis De La Torreubieta, Michele Pagano, Azad Bonni, Guangchao Liu, Antonio IavaroneAbstract: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.
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id2 specifically alters regulation of the cell cycle by tumor suppressor proteins
Molecular and Cellular Biology, 1996Co-Authors: Anna Lasorella, Antonio Iavarone, Mark A IsraelAbstract:Cells which are highly proliferative typically lack expression of differentiated, lineage-specific characteristics. Id2, a member of the helix-loop-helix (HLH) protein family known to inhibit cell differentiation, binds to the retinoblastoma protein (pRb) and abolishes its growth-suppressing activity. We found that Id2 but not Id1 or Id3 was able to bind in vitro not only pRb but also the related proteins p107 and p130. Also, an association between Id2 and p107 or p130 was observed in vivo in transiently transfected Saos-2 cells. In agreement with these results, expression of Id1 or Id3 did not affect the block of cell cycle progression mediated by pRb. Conversely, expression of Id2 specifically reversed the cell cycle arrest induced by each of the three members of the pRb family. Furthermore, the growth-suppressive activities of cyclin-dependent kinase inhibitors p16 and p21 were efficiently antagonized by high levels of Id2 but not by Id1 Id3. Consistent with the role of p16 as a selective inhibitor of pRb and pRb-related protein kinase activity, p16-imposed cell cycle arrest was completely abolished by Id2. Only a partial reversal of p21-induced growth suppression was observed, which correlated with the presence of a functional pRb. We also documented decreased levels of cyclin D1 protein and mRNA and the loss of cyclin D1-cdk4 complexes in cells constitutively expressing Id2. These data provide evidence for important Id2-mediated alterations in cell cycle components normally involved in the regulatory events of cell cycle progression, and they highlight a specific role for Id2 as an antagonist of multiple tumor suppressor proteins.
Anna Lasorella - One of the best experts on this subject based on the ideXlab platform.
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transcription factor id2 prevents e proteins from enforcing a naive t lymphocyte gene program during nk cell development
Science immunology, 2018Co-Authors: Erin C Zook, Anna Lasorella, Mikael Sigvardsson, Renee F De Pooter, Mihalis Verykokakis, Aimee M Beaulieu, Mark Maienscheincline, Joseph C Sun, Barbara L KeeAbstract: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.
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transcriptional regulator id2 is required for the cd4 t cell immune response in the development of experimental autoimmune encephalomyelitis
Journal of Immunology, 2012Co-Authors: Yenyu Lin, Anna Lasorella, Antonio Iavarone, Mary Elizabeth Jonesmason, Makoto Inoue, Mari L Shinohara, Yuan ZhuangAbstract:An effective immune response to Ag challenge is critically dependent on the size of the effector cell population generated from clonal activation of Ag-specific T cells. The transcription network involved in regulating the size of the effector population, particularly for CD4 Th cells, is poorly understood. In this study, we investigate the role of Id2, an inhibitor of E protein transcription factors, in the generation of CD4 effectors. Using a T cell-specific conditional Id2 knockout mouse model, we show that inhibitor of DNA binding (Id)2 is essential for the development of experimental autoimmune encephalomyelitis. Although Ag-specific and IL-17–producing CD4 T cells are produced in these mice, the activated CD4 T cells form a smaller pool of effector cells in the peripheral lymphoid organs, exhibit reduced proliferation and increased cell death, and are largely absent in the CNS. In the absence of Id2, E protein targets, including the proapoptotic protein Bim and SOCS3, are expressed at higher levels among activated CD4 T cells. This study reveals a critical role of Id2 in the control of effector CD4 T cell population size and the development of a Th17-mediated autoimmune disease.
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id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3f
Cancer Research, 2010Co-Authors: Dhara N Amin, Akio Shimizu, Anna Lasorella, Antonio IavaroneAbstract: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.
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degradation of id2 by the anaphase promoting complex couples cell cycle exit and axonal growth
Nature, 2006Co-Authors: Anna Lasorella, Judith Stegmuller, Daniele Guardavaccaro, Maria Stella Carro, Gerson Rothschild, Luis De La Torreubieta, Michele Pagano, Azad Bonni, Antonio IavaroneAbstract: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.
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degradation of id2 by the anaphase promoting complex couples cell cycle exit and axonal growth
Nature, 2006Co-Authors: Anna Lasorella, Judith Stegmuller, Daniele Guardavaccaro, Maria Stella Carro, Gerson Rothschild, Luis De La Torreubieta, Michele Pagano, Azad Bonni, Guangchao Liu, Antonio IavaroneAbstract: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.
Robert Benezra - One of the best experts on this subject based on the ideXlab platform.
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Id1, Id2, Id3, and ID4 in adult mouse brain lateral wall V-SVZ neural stem cells
2020Co-Authors: Hyung-song Nam, Mario Capecchi, Robert BenezraAbstract:An R script to analyze the Mizrak et al., 2019 dataset.Clusters. Selected marker genes RNA in clusters.Markers for selected subclusters identified by Seurat.To validate the AverageExpression command results, RT-qPCR measurements from Morizur et al., 2018 (https://doi.org/10.1016/j.stemcr.2018.06.005) were utilized. The trends were very similar, suggesting that normalized scRNA-seq datasets can also reveal the average RNA expression level of cell populations otherwise obtained by FACS sorting and RT-qPCR.The relative RNA abundance in the lateral wall V-SVZ qNSC's of Id1, Id2, Id3, and ID4 seems to be Id2 > Id3 > ID4 > Id1. How the RNA levels correlate to protein levels is unclear, although the Id1 protein in particular was measured directly by knock-in C-terminal fusion of the Venus yellow fluorescent protein (https://doi.org/10.1016/j.stem.2009.08.017, https://doi.org/10.1016/j.ccr.2011.11.025, https://doi.org/10.1242/jcs.096198, https://doi.org/10.1016/j.stemcr.2014.09.012, https://doi.org/10.7554/elife.01197, https://doi.org/10.1016/j.devcel.2019.05.032). ==============The material from my PhD thesis work I put up here after going through them again after more than ten years are (1) copied and pasted from my PhD thesis, (2) data from my PhD thesis work (Immunofluorescence images, Southern blots, PCR gels, restriction digests, and flow data), and (3) re-analysis of the data using modern software (flow data and sequence analyses for the knock-in allele targeting vectors and Southern blots).Mirax epifluorescence scans of coronal sections of >6 week old wildtype mouse brain. Id1 (green). Ki-67 or Mcm2 (red). DAPI (blue). Id1 and Ki-67 or Mcm2 merged.A confocal z-stack from coronal section of a wildtype mouse brain V-SVZ, >6 week old. A maximum projection image montage and a movie of the z-stack. Id1 (green). Mcm2 (red). DAPI (blue).A confocal z-stack from coronal section of a wildtype mouse brain V-SVZ, >6 week old. Perfused 48 h after the cessation of Ara-C infusion for 6 days, as described in Nam and Benezra, 2009. EdU was injected 30 min before the perfusion. A maximum projection image montage and a movie of the z-stack. Id1 (green). EdU (red). DAPI (blue). The small dots are probably non-specific protein precipitates from the block buffer.A confocal z-stack from coronal section of a wildtype mouse brain V-SVZ, >6 week old. A maximum projection image montage and movies of the z-stack. Id1 (green). S100beta (red). DAPI (blue).Some self-explanatory images.Production of the Id1-floxed allele mouse (http://www.informatics.jax.org/allele/MGI:4366910), the Id1-Venus allele mouse (http://www.informatics.jax.org/allele/MGI:4366905), the Id1-IRES-creERT2 allele mouse (http://www.informatics.jax.org/allele/MGI:4366863), and the ROSA26-StLa allele mouse (http://www.informatics.jax.org/allele/MGI:4366911).There were two variants of the Id1 targeting vector. The first variant utilized a long 5' arm and a DTA cassette. The second variant utilized a shorter 5' arm and DTA and TK cassettes. The lengths of the homology arms in the first variant were from Yan et al., 1997 (https://doi.org/10.1128/mcb.17.12.7317). The actual genomic DNA was subcloned from RPCI-23 C57BL/6J mouse genome BAC library using recombineering.I would put up the Sanger sequencing files of the targeting vectors if I could, but I'm not sure if I have the intellectual property rights to do that. Regardless, I have re-analyzed the sequencing results of the Id1 targeting vectors, and did not find any errors. I did not go through the ROSA26-StLa targeting vector sequencing again. By the way, these targeting vectors were constructed on a high copy backbone. With the large genomic insert, the plasmid DNA of the final construct was very difficult to prepare because the E. coli harboring it grew very slowly, and the plasmid was prone to rearrangements by recombination. This sometimes happens - see https://www.addgene.org/61580/ for comments from the Hongkui Zeng laboratory. To make it work, plasmid prep from every culture of the clone had to be checked for recombination by restriction digests before using. Preps of recombined plasmids had to be discarded. The low copy backbone plasmids are much easier to work with because they don't behave this way. For anybody still doing gene targeting, I would recommend them (see https://doi.org/10.6084/m9.figshare.c.5277341.v12 for links to Addgene).Flow cytometry data. The figure pdf shows the gates that were utilized to detect Id1-Venus+ cells from dissociated V-SVZ cells as well as Id1-Venus+ cells in cultured V-SVZ cells. The zip files are the actual FCS files. The file names were modified to be descriptive.Tried a wider gate for Id1-Venus and Gfap detection. Could see more in the double-positive gate, but the larger cells might be more autofluorescent.As in the paper, there were neural Id1-Venus+ cells as well as endothelial Id1-Venus+ cells in the V-SVZ (mice >6 weeks of age). Culturing the V-SVZ cells in neurosphere-forming media with EGF and FGF-2 was a quick way to enrich for the neural lineage cells without FACS, etc. In the cultures of neural lineage cells of the V-SVZ thus obtained, there were Id1-Venus+ and Id1-Venus- cells that could be discerned. The Id1-Venus-high cells formed self-renewing neurospheres, etc as described in the paper. As an aside, the Id1-Venus fusion protein reporter actually generated a very sensitive read-out of the Id1 protein. These are why I think so. The Id1 protein was very difficult to detect in the brain tissue (i.e., no signal with conventional indirect immunofluorescence in both cell types). I could only visualize it after Tyramide Signal Amplification. The labeling efficiency with the Id1IRES-creERT2 allele was also somewhat low. Although other reasons are also possible, these suggested to me low protein expression level. Then, there may not be so many copies of the Id1-Venus protein in the cell. Yet, it was detectable with flow cytometers. If the Discussion of the Nam and Benezra, 2009 paper wasn't clear, I note here that even though the absolute level of the Id1 protein may be low, its level is highest in the stem/progenitor cells if one considers the relative levels along the neurogenic lineage.Id1-Venus fluorescence from adherent NSPC cultures.Two confocal images of YFP+ cells from ventricular wall whole mount of Id1IRES-creERT2/+; ROSA26LSL-YFP/+ mice that were scored to be "B1" cells from Mirzadeh et al., 2008 (https://doi.org/10.1016/j.stem.2008.07.004). Previously, the whole mount immunfluorescence technique wasn't as optimized as it is now, so the images weren't so clear. However, putting the previous work in context with my more recent work, what is clear is that the cells labeled by the Id1IRES-creERT2 allele were different from the cells labeled by the Lrig1T2A-iCreERT2 allele (see https://doi.org/10.6084/m9.figshare.12731900.v8). So how is it possible to get Lrig1 out of Id1high cells when they label cells with different morphologies? Although it wasn't apparent with the previous technique, more recent results suggest that Id1 also labels the cells labeled by Lrig1 (unpublished preliminary observation). So, a working model is that there are at least two different types of stem cells: Id1 reveals both, whereas Lrig1 reveals mostly one subset. ==============Id1+ cells outside the V-SVZ.Two coronal section images from hippocampus of Id1IRES-creERT2/+; ROSA26StLa/+ mouse. 1 month after tamoxifen inductions. Non-endothelial X-gal+ cells (from tauLacZ) in the dentate gyrus.A confocal image from coronal section of hippocampus of Id1IRES-creERT2/+; ROSA26StLa/+ mouse. 1 month after tamoxifen inductions. Tau-b-gal (green), NeuN (red), and DAPI (blue).A confocal image from a coronal section of wildtype mouse embryo (~E12.5) spinal cord. Id1 (green), Nestin (red), and DAPI (blue).
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id genes mediate tumor reinitiation during breast cancer lung metastasis
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Gaorav P Gupta, Robert Benezra, Paola De Candia, Edi Brogi, Vivek Mittal, Jonathan Perk, Swarnali Acharyya, Katia Todorovamanova, William L Gerald, Joan MassagueAbstract:The establishment of distant metastases depends on the capacity of small numbers of cancer cells to regenerate a tumor after entering a target tissue. The mechanisms that confer this capacity remain to be defined. Here we identify a role for the transcriptional inhibitors of differentiation Id1 and Id3 as selective mediators of lung metastatic colonization in the triple negative [TN, i.e., lacking expression of estrogen receptor and progesterone receptor, and lacking Her2 (human epidermal growth factor receptor 2) amplification] subgroup of human breast cancer. Although broad expression of Id1 has recently been documented in tumors of the rare metaplastic subtype, here we report that rare Id1-expressing cells are also present in the more common TN subset of human breast tumors but not in other subtypes. We also provide evidence that Id1 expression is enriched in clinically obtained hormone receptor negative lung metastases. Functional studies demonstrate that Id1 and its closely related family member Id3 are required for tumor initiating functions, both in the context of primary tumor formation and during metastatic colonization of the lung microenvironment. In vivo characterization of lung metastatic progression reveals that Id1 and Id3 facilitate sustained proliferation during the early stages of metastatic colonization, subsequent to extravasation into the lung parenchyma. These results shed light on the proliferative mechanisms that initiate metastatic colonization, and they implicate Id1 and Id3 as mediators of this malignant function in the TN subgroup of breast cancers.
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id sustains hes1 expression to inhibit precocious neurogenesis by releasing negative autoregulation of hes1
Developmental Cell, 2007Co-Authors: Nengyin Sheng, François Guillemot, Yoshifumi Yokota, Robert Benezra, Ryoichiro Kageyama, Wei Bian, Naihe JingAbstract:Negative bHLH transcription factor Hes1 can inhibit neural stem cells (NSCs) from precocious neurogenesis through repressing proneural gene expression; therefore, sustenance of Hes1 expression is crucial for NSC pool maintenance. Here we find that Ids, the dominant-negative regulators of proneural proteins, are expressed prior to proneural genes and share an overlapping expression pattern with Hes1 in the early neural tube of chick embryos. Overexpression of Id2 in the chick hindbrain upregulates Hes1 expression and inhibits proneural gene expression and neuronal differentiation. By contrast, Hes1 expression decreases, proneural gene expression expands, and neurogenesis occurs precociously in Id1;Id3 double knockout mice and in Id1-3 RNAi-electroporated chick embryos. Mechanistic studies show that Id proteins interact directly with Hes1 and release the negative feedback autoregulation of Hes1 without interfering with its ability to affect other target genes. These results indicate that Id proteins participate in NSC maintenance through sustaining Hes1 expression in early embryos.
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ID4 messenger rna and estrogen receptor expression inverse correlation in human normal breast epithelium and carcinoma
Human Pathology, 2006Co-Authors: Paola De Candia, Robert Benezra, Muzaffar Akram, Edi BrogiAbstract:Id (inhibitor of DNA binding) 4 is a member of the Id family of proteins (Id1-ID4), which function as dominant-negative regulators of basic helix-loop-helix transcription factors. Id factors are involved in numerous cell processes, including cell proliferation, differentiation, and tumorigenesis. We assessed the expression of ID4 messenger RNA (mRNA) in invasive mammary carcinoma from 31 patients, as well as in 21 cases of ductal carcinoma in situ, in 9 lymph node metastases, and in the morphologically normal epithelium adjacent to the carcinoma from the same subjects. In addition, we evaluated ID4 mRNA in atypical ductal hyperplasia from 5 other women and in normal breast tissue from yet another 5 women with no history of breast malignancy or atypia. The distribution of ID4 signal was assessed in relation to that of estrogen receptor (ER) in all samples and correlated with the Her-2 status of the carcinomas. ID4 mRNA was present in the normal ER-negative mammary epithelium in all cases; in contrast, the ER-positive cells present in the normal breast were ID4 negative. ID4 mRNA was not detected in atypical ductal hyperplasia, in 22 of the 23 cases of ductal carcinoma in situ, and in 27 of the 31 invasive carcinomas (P = .0008), all of which were ER positive. Conversely, 3 of the 31 invasive carcinomas were ID4 positive and ER negative. Only 1 ER-positive invasive carcinoma showed focal reactivity for ID4. The expression of ID4 in metastatic carcinoma paralleled that of the primary tumor. No correlation was apparent between ID4 and Her-2. Our data show that ID4 is constitutively expressed in the normal human mammary epithelium but is suppressed in ER-positive breast carcinomas and preneoplastic lesions. In contrast, ER-negative carcinomas appear to be ID4 positive. These results support a possible role of ID4 as a tumor suppressor factor in the human breast and suggest that the expression of ID4 in the mammary ductal epithelium may be regulated by estrogen. Further investigations are required to define the functions of ID4 in the human normal breast and in mammary neoplasia.
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angiogenesis impairment in id deficient mice cooperates with an hsp90 inhibitor to completely suppress her2 neu dependent breast tumors
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Paola De Candia, Edi Brogi, David B Solit, Dilip Giri, Peter M Siegel, Adam B Olshen, William J Muller, Neal Rosen, Robert BenezraAbstract:Id proteins bind basic helix–loop–helix transcription factors and function as dominant negative inhibitors of gene expression. Id1 and Id3 are required for the recruitment of bone marrow-derived endothelial cell precursors and tumors transplanted into Id-deficient mice demonstrate impaired angiogenesis. Mouse mammary tumor virus–neu mice were bred with Id1–/–Id3+/– mice to ascertain the role of Id1 and Id3 in mammary tumorigenesis in a more physiologically relevant model. In mammary tumors from these mice, Id1 and Id3 expression was restricted to the vascular endothelium. Id1 and Id3 deficiency did not prevent or delay tumor formation but did alter tumor phenotype. The tumors that developed in the Id-deficient mice were larger and cystic with a viable rim of tumor cells surrounding a nonviable core of cellular debris. The Hsp90 chaperone protein is required for cellular survival under condition of environmental stress and for the stability of the neu oncogene. 17-Allylamino-17-demethoxygeldanamycin, an Hsp90 inhibitor, was used to treat these mice. Whereas 17-allylamino-17-demethoxygeldanamycin only modestly delayed the growth of established mammary tumors in WT mice for Id, tumor suppression was dramatically more effective in an Id1- or Id3-deficient background. These data suggest that tumorigenesis can occur in a background of defective angiogenesis but that tumors developing in such an environment may be especially sensitive to inhibitors of neu and stress-activated survival pathways. Thus angiogenesis inhibitors in combination with inhibitors of Hsp90 function should be evaluated for the treatment of advanced breast cancer.
Qingyin Zheng - One of the best experts on this subject based on the ideXlab platform.
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hearing loss in id1 id3 and id1 id3 mice is associated with a high incidence of middle ear infection otitis media
Frontiers in Genetics, 2021Co-Authors: Qingyin Zheng, Tihua Zheng, Aizhen Zhang, Bin Yan, Zhaoqiang Zhang, Yan ZhangAbstract: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).
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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', 2021Co-Authors: Qingyin Zheng, Tihua Zheng, Aizhen Zhang, Bin Yan, Zhaoqiang Zhang, Yan ZhangAbstract: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).
Jaideep Chaudhary - One of the best experts on this subject based on the ideXlab platform.
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ID4 promotes ar expression and blocks tumorigenicity of pc3 prostate cancer cells
Biochemical and Biophysical Research Communications, 2016Co-Authors: Shravan Kumar Komaragiri, Dhanushka Hewa Bostanthirige, Derrick J Morton, Divya Patel, Jugal Joshi, Sunil Upadhyay, Jaideep ChaudharyAbstract:Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, we examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co-regulators that may determine the final outcome of AR function.
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id1 and id3 expression is associated with increasing grade of prostate cancer id3 preferentially regulates cdkn1b
Cancer Medicine, 2012Co-Authors: Pankaj Sharma, Divya Patel, Jaideep ChaudharyAbstract:As transcriptional regulators of basic helix–oop–helix (bHLH) transcription and non-bHLH factors, the inhibitor of differentiation (Id1, Id2, Id3, and ID4) proteins play a critical role in coordinated regulation of cell growth, differentiation, tumorigenesis, and angiogenesis. Id1 regulates prostate cancer (PCa) cell proliferation, apoptosis, and androgen independence, but its clinical significance in PCa remains controversial. Moreover, there is lack of evidence on the expression of Id2 and Id3 in PCa progression. In this study we investigated the expression of Id2 and Id3 and reevaluated the expression of Id1 in PCa. We show that increased Id1 and Id3 protein expression is strongly associated with increasing grade of PCa. At the molecular level, we report that silencing either Id1 or Id3 attenuates cell cycle. Although structurally and mechanistically similar, our results show that both these proteins are noncompensatory at least in PCa progression. Moreover, through gene silencing approaches we show that Id1 and Id3 primarily attenuates CDKN1A (p21) and CDKN1B (p27), respectively. We also demonstrate that silencing Id3 alone significantly attenuates proliferation of PCa cells as compared with Id1. We propose that increased Id1 and Id3 expression attenuates all three cyclin-dependent kinase inhibitors (CDKN2B, -1A, and -1B) resulting in a more aggressive PCa phenotype.
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the helix loop helix inhibitor of differentiation id proteins induce post mitotic terminally differentiated sertoli cells to re enter the cell cycle and proliferate
Biology of Reproduction, 2005Co-Authors: Jaideep Chaudhary, Ingrid Sadlerriggleman, Jacquelyn M Ague, Michael K SkinnerAbstract:Prior to puberty the Sertoli cells undergo active cell proliferation, and at the onset of puberty they become a terminally differentiated postmitotic cell population that support spermatogenesis. The molecular mechanisms involved in the postmitotic block of pubertal and adult Sertoli cells are unknown. The four known helix-loop-helix ID proteins (i.e., Id1, Id2, Id3, and ID4) are considered dominant negative regulators of cellular differentiation pathways and act as positive regulators of cellular proliferation. ID proteins are expressed at low levels by postpubertal Sertoli cells and are transiently induced by serum. The hypothesis tested was that ID proteins can induce a terminally differentiated postmitotic Sertoli cell to reenter the cell cycle if they are constitutively expressed. To test this hypothesis, ID1 and ID2 were stably integrated and individually overexpressed in postmitotic rat Sertoli cells. Overexpression of ID1 or ID2 allowed postmitotic Sertoli cells to reenter the cell cycle and undergo mitosis. The cells continued to proliferate even after 300 cell doublings. The functional markers of Sertoli cell differentiation such as transferrin, inhibin alpha, Sert1, and androgen binding protein (ABP) continued to be expressed by the proliferating Sertoli cells, but at lower levels. FSH receptor expression was lost in the proliferating Sertoli cell-Id lines. Some Sertoli cell genes, such as cyclic protein 2 (cathepsin L) and Sry-related HMG box protein-11 (Sox11) increase in expression. At no stage of proliferation did the cells exhibit senescence. The expression profile as determined with a microarray protocol of the Sertoli cell-Id lines suggested an overall increase in cell cycle genes and a decrease in growth inhibitory genes. These results demonstrate that overexpression of ID1 and ID2 genes in a postmitotic, terminally differentiated cell type have the capacity to induce reentry into the cell cycle. The observations are discussed in regards to potential future applications in model systems of terminally differentiated cell types such as neurons or myocytes.
