The function of E- and id proteins in lymphocyte development

Engel, Isaac; Murre, Cornelis

doi:10.1038/35105060

Cited by 186 publications

(183 citation statements)

References 68 publications

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“…This Tax-induced E2A protein silencing mechanism is reminiscent of that associated with the AML-ETO fusion protein that inhibits transcriptional activation by E proteins through stable interactions that preclude recruitment of the coactivators (47). This mechanism is therefore fundamentally distinct from that used by Id proteins which, through interactions with DNA binding regions of E2A proteins, block binding to the promoter (11,12). During early thymocyte development, the E2A proteins function as gatekeepers to arrest both differentiation and proliferation of thymocytes with defects in the assembly of the pre-TCR complex.…”

Section: Discussionmentioning

confidence: 94%

“…Before reverse transcription, RNAs were first treated with 10 U of RNase-free DNase I (QIAGEN) for 30 min at 27°C and then for 10 min at 60°C. This RNA sample was then reverse transcribed at 42°C for 1 h in a total volume of 20 l reaction buffer (50 mM Tris, pH 8.3, 30 mM KCl, 3 mM MgCl 2 , 10 mM dithiothreitol) containing 100 U of SuperScriptII RNase H Ϫ reverse transcriptase (RT; Invitrogen), 100 pmol of oligo(dT) [12][13][14][15][16][17][18] (Invitrogen), and 20 U of RNase inhibitor (Rnasin; Promega). A reaction without RT was performed in parallel to serve as control for the absence of DNA contamination.…”

Section: Cells and Plasmidsmentioning

confidence: 99%

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Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Wencker

Sausse

Derse

et al. 2007

J Virol

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The human pre-T-cell receptor alpha (TCR␣; pT␣) gene encodes a polypeptide which associates with the TCR␤ chain and CD3 molecules to form the pre-TCR complex. The surface expression of the pre-TCR is pT␣ dependent, and signaling through this complex triggers an early ␣␤ T-cell developmental checkpoint inside the thymus, known as ␤-selection. E2A transcription factors, which are involved at multiple stages of T-cell development, regulate the transcription of the pT␣ gene. Here we show that the regulatory protein Tax of the human T-cell leukemia virus type 1 (HTLV-1) efficiently suppresses the E47-mediated activation of the pT␣ promoter. Furthermore, we report that in Tax lentivirally transduced human MOLT-4 T cells, which constitutively express the pT␣ gene, the amount of pT␣ transcripts decreases. Such a decrease is not observed in MOLT-4 cells transduced by a vector encoding the Tax mutant K88A, which is unable to interact with p300. These data underline that Tax inhibits pT␣ transcription by recruiting this coactivator. Finally, we show that the expression of Tax in human immature thymocytes results in a decrease of pT␣ gene transcription but does not modify the level of E47 transcripts. These observations indicate that Tax, by silencing E proteins, down-regulates pT␣ gene transcription during early thymocyte development. They further provide evidence that Tax can interfere with an important checkpoint during T-cell differentiation in the thymus.

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Section: Discussionmentioning

confidence: 94%

Section: Cells and Plasmidsmentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Wencker

Sausse

Derse

et al. 2007

J Virol

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“…Id proteins are known to negatively regulate another class of HLH proteins, the E-proteins, by inhibiting these proteins' ability to bind DNA. The E-proteins play crucial roles in survival, proliferation and differentiation of lymphocytes, and interestingly, they have been shown to both promote and inhibit growth at different stages of lymphocyte development [9,10]. It has been shown that T cell development is partially blocked at the CD4 -CD8 -double-negative 1 stage in E2A-deficient mice [43].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have pointed toward members of the inhibitor of DNA binding (Id) protein family, a class of helix-loop-helix (HLH) proteins, as important targets for BMP signalling [5][6][7][8]. HLH proteins act as transcriptional regulators and are essential factors for lymphoid development and function [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-b superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4 + T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4 + T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

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“…Recent studies have also highlighted their role in cellular senescence (3,4) and in cell fate decisions in cells of specialized lineages such as lymphocytes (5) (reviewed in Ref. 6), vascular endothelial cells (7,8), and neuronal cells (7,9). The four members of the Id protein family (Id1-Id4) function by directly associating with and modulating the activity of several families of transcriptional regulators (1, 10 -12).…”

mentioning

confidence: 99%

Id Proteins Negatively Regulate Basic Helix-Loop-Helix Transcription Factor Function by Disrupting Subnuclear Compartmentalization

O’Toole

Inoue

Emerson

et al. 2003

Journal of Biological Chemistry

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Id helix-loop-helix (HLH) proteins act as global regulators of metazoan cell fate, cell growth, and differentiation. They heterodimerize with and inhibit the DNA-binding function of members of the basic helixloop-helix (bHLH) family of transcription factors. Using real time fluorescence microscopy techniques in single living cells, we show here that nuclear pools of chromatin-associated bHLH transcription factor are freely exchangeable and in constant flux. The existence of a dynamic equilibrium between DNA-bound and free bHLH protein is also directly demonstrable in vitro. By contrast, Id protein is not associated with any subcellular, macromolecular structures and displays a more highly mobile, diffuse nuclear-cytoplasmic distribution. When co-expressed with antagonist Id protein, the chromatinassociated sublocalization of bHLH protein is abolished, and there is an accompanying 100-fold increase in its nuclear mobility to a level expected for freely diffusible Id-bHLH heterodimer. These results suggest that nuclear Id protein acts by sequestering pools of transiently diffusing bHLH protein to prevent reassociation with chromatin domains. Such a mechanism would explain how Id proteins are able to overcome the large DNAbinding free energy of bHLH proteins that is necessary to accomplish their inhibitory effect.Id proteins function as global regulators of cell fate determination. They play a pivotal role in the coordinate regulation of gene expression during cell growth/cell cycle control, differentiation, and tumorigenesis (reviewed in Refs. 1 and 2). Recent studies have also highlighted their role in cellular senescence (3, 4) and in cell fate decisions in cells of specialized lineages such as lymphocytes (5) (reviewed in Ref. 6), vascular endothelial cells (7,8), and neuronal cells (7, 9). The four members of the Id protein family (Id1-Id4) function by directly associating with and modulating the activity of several families of transcriptional regulators (1, 10 -12). However, compelling biochemical and genetic data implicate members of the ubiquitously expressed Class A, basic helix-loop-helix (bHLH) 1 family of "E proteins" as the most important heterodimerization targets for Id proteins in the coordinate regulation of gene expression during cell fate determination (1, 2, 13, 14). In mammals, there are three E protein family genes, E2A (encoding three alternatively spliced variants, E12, E47, and E2-5), E2-2 (ITF2), and HEB (14). The E proteins bind to a consensus "E-box" recognition sequence, present in the transcriptional control regions of numerous cellular genes, either as a homodimer or, more commonly, as a heterodimeric partner with a member of the much larger family of tissue-specific, Class B bHLH proteins. Id proteins lack a basic, DNA-binding domain, and they heterodimerize avidly (via their HLH domain) with bHLH E proteins (13) to prevent the latter from binding to DNA (1,14). Since E proteins are obligate heterodimerization partners for tissue-specific bHLH proteins, this provides a common mechani...

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The function of E- and id proteins in lymphocyte development

Cited by 186 publications

References 68 publications

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Id Proteins Negatively Regulate Basic Helix-Loop-Helix Transcription Factor Function by Disrupting Subnuclear Compartmentalization

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