High Incidence of T-Cell Tumors in E2A-Null Mice and E2A/Id1 Double-Knockout Mice

Yan, Wei; Young, Alison Z.; Soares, Vera; Kelley, Robert J.; Benezra, Robert; Zhuang, Yuan

doi:10.1128/mcb.17.12.7317

Cited by 215 publications

(213 citation statements)

References 47 publications

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“…This finding is consistent with the observation that E2A-deficient mice developed T-cell lymphoma with a relatively high frequency (Bain et al, 1997;Yan et al, 1997). LYL1 only partially inhibits E2A function, so that the residual E2A activity may be responsible for the low incidence of LYL1-induced lymphoma.…”

Section: Discussionsupporting

confidence: 91%

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

et al. 2007

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LYL1, a member of the class II basic helix-loop-helix transcription factors, is aberrantly expressed in a fraction of human T-cell acute lymphoblastic leukemia. Here, we generated transgenic mice ubiquitously overexpressing LYL1 using a construct expressing full-length cDNA driven by a human elongation factor 1a promoter. Four independent lines exhibiting high LYL1 expression were established. Of these transgenic mice, 96% displayed loss of hair with a short kinked tail. Furthermore, 30% of them developed malignant lymphoma, with an average latent period of 352 days. In these mice, histological examination revealed tumor cell infiltration in multiple organs and immunohistochemical analysis showed that the infiltrated tumor cells were either CD3 or CD45R/B220-positive; fluorescence-activated cell sorter analysis indicated that each tumor consisted either of mainly CD4, CD8 double-positive T cells or mature B cells; the clonality of LYL1-induced lymphoma was confirmed by T-cell receptor rearrangement and immunoglobulin heavychain gene rearrangement analyses. Mammalian twohybrid analysis and luciferase assay suggested that excess LYL1 blocked the dimerization of E2A and thus inhibited the regulatory activity of E2A on the CD4 promoter. Reverse transcription-polymerase chain reaction results showed that the expression of certain E2A/HEB target genes was downregulated. Taken together, our results provide direct evidence that aberrant expression of LYL1 plays a role in lymphomagenesis.

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Section: Discussionsupporting

confidence: 91%

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

et al. 2007

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“…Tissue-specific bHLH proteins associated with E2A proteins include the MyoD family involved in skeletal muscle differentiation (Weintraub, 1993), the achaete-scute family involved in neuronal differentiation (Guillemot et al, 1993), and SCL/TAL which is involved in hematopoiesis (Hsu et al, 1991). The E2A proteins are also required for lymphocyte development, and have also been implicated in cell growth, apoptosis and lymphomagenesis (Bain et al, 1994;Peverali et al, 1994;Yan et al, 1997;Quong et al, 2002;Lazorchak et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

E2A protein degradation by the ubiquitin-proteasome system is stage-dependent during muscle differentiation

et al. 2006

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The E2A proteins are basic helix-loop-helix transcription factors that regulate proliferation and differentiation in many cell types. In muscle cells, the E2A proteins form heterodimers with muscle regulatory factors such as MyoD, which then bind to DNA and regulate the transcription of target genes essential for muscle differentiation. We now demonstrate that E2A proteins are primarily localized in the nucleus in both C2C12 myoblasts and myotubes, and are degraded by the ubiquitin proteasome system evidenced by stabilization following treatment with the proteasome inhibitor, MG132. During the differentiation from myoblast to myotube, the cellular abundance of E2A proteins is relatively unaltered, despite significant changes (each B5-fold) in the relative rates of protein synthesis and protein degradation via the ubiquitin-proteasome system. The rate of ubiquitin-proteasome-mediated E2A protein degradation depends on the myogenic differentiation state (t½B2 h in proliferating myoblasts versus t½>10 h in differentiated myotubes), and is also associated with cell cycle in non-muscle cells. Our findings reveal an important role for both translational and post-translational regulatory mechanisms in mediating the complex program of muscle differentiation determined by the E2A proteins.

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“…Id proteins function as global regulators of gene expression during cell growth and differentiation (reviewed in Ruzinova and Benezra, 2003;Wong et al, 2004). Recent studies have highlighted their role in differentiation of specialized lineages such as lymphocytes (Sun, 1994;Yan et al, 1997), granulocyte (Buitenhuis et al, This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-10 -1057) on February 20, 2008. 2005), vascular endothelial cells (Pammer et al, 2004;Kim et al, 2007), myocytes (Alway et al, 2002;Liu et al, 2002), cardiac myocytes (Ding et al, 2006b), and neuronal cells (Jen et al, 1997;Lyden et al, 1999;Nakashima et al, 2001). Id proteins, which lack a DNA binding domain, associate with other transcriptional factors and prevent them from binding DNA or forming active heterodimers (Benezra et al, 1990b).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

p204 Protein Overcomes the Inhibition of Core Binding Factor α-1–mediated Osteogenic Differentiation by Id Helix-Loop-Helix Proteins

Luan

Yang

et al. 2008

MBoC

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Id proteins play important roles in osteogenic differentiation; however, the molecular mechanism remains unknown. In this study, we established that inhibitor of differentiation (Id) proteins, including Id1, Id2, and Id3, associate with core binding factor ␣-1 (Cbfa1) to cause diminished transcription of the alkaline phosphatase (ALP) and osteocalcin (OCL) gene, leading to less ALP activity and osteocalcin (OCL) production. Id acts by inhibiting the sequence-specific binding of Cbfa1 to DNA and by decreasing the expression of Cbfa1 in cells undergoing osteogenic differentiation. p204, an interferon-inducible protein that interacts with both Cbfa1 and Id2, overcame the Id2-mediated inhibition of Cbfa1-induced ALP activity and OCL production. We show that 1) p204 disturbed the binding of Id2 to Cbfa1 and enabled Cbfa1 to bind to the promoters of its target genes and 2) that p204 promoted the translocation from nucleus to the cytoplasm and accelerated the degradation of Id2 by ubiquitin-proteasome pathway during osteogenesis. Nucleus export signal (NES) of p204 is required for the p204-enhanced cytoplasmic translocation and degradation of Id2, because a p204 mutant lacking NES lost these activities. Together, Cbfa1, p204, and Id proteins form a regulatory circuit and act in concert to regulate osteoblast differentiation. INTRODUCTIONThe differentiation of uncommitted mesenchymal cells to osteoblasts is a fundamental process in embryonic development and bone repair. The bone morphogenetic proteins (BMPs) are important regulators of this process (Heldin et al., 1997;Miyazono et al., 2000). They function by binding cell surface receptors; signaling by Smad proteins; and activating bone-specific genes, including core binding factor ␣-1 (Cbfa1) (Ducy, 2000;Miyazono et al., 2001;Attisano and Wrana, 2002). This process is positively or negatively regulated by a variety of coactivators and corepressors (Ducy et al., 2000;Miyazono et al., 2001;Attisano and Wrana, 2002). Cbfa1, also known as Runx2, PeBP2␣A, Osf2, or AML3, is a member of the runt family of transcription factors. It is an essential transcription factor of osteoblast and bone formation (Ducy, 2000). During skeletal development, Cbfa1 is observed first in early mesenchymal condensations, and it is then principally expressed in osteoblasts . Cbfa1 Ϫ/Ϫ mice exhibit a complete lack of ossification, and they die immediately after birth (Komori et al., 1997). Cbfa1 maintains osteoblastic function by regulating the expression of several bone-specific genes such as osteopontin and osteocalcin and by controlling bone extracellular matrix deposition (Ducy, 2000). Mutations in Cbfa1 are found in 65-80% of individuals with cleidocranial dysplasia (CCD) (Lee et al., 1997;Mundlos and Olsen, 1997;Zhou et al., 1999). The molecular mechanisms underlying the pathogenesis of CCD are not completely defined. Some mutations of Cbfa1 abolish its DNA binding activity (Lee et al., 1997;Zhou et al., 1999) and others disturb the association of Cbfa1 to its binding partners, including Sma...

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High Incidence of T-Cell Tumors in E2A-Null Mice and E2A/Id1 Double-Knockout Mice

Cited by 215 publications

References 47 publications

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

E2A protein degradation by the ubiquitin-proteasome system is stage-dependent during muscle differentiation

p204 Protein Overcomes the Inhibition of Core Binding Factor α-1–mediated Osteogenic Differentiation by Id Helix-Loop-Helix Proteins

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